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John Digiovanni - One of the best experts on this subject based on the ideXlab platform.
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evaluation of pentacyclic triterpenes found in perilla frutescens for inhibition of Skin Tumor promotion by 12 o tetradecanoylphorbol 13 acetate
Oncotarget, 2015Co-Authors: Jiyoon Cho, Thomas J. Slaga, Okkyung Rho, Lisa Tremmel, Andrew M Camelio, Dionicio Siegel, John DigiovanniAbstract:A series of pentacyclic tritperpenes found in Perilla frutescens (P. frutescens), including ursolic acid (UA), oleanolic acid (OA), corosolic acid (CA), 3-epi-corosolic acid (3-epiCA), maslinic acid (MA), and 3-epi-maslinic acid (3-epiMA) were evaluated for their effects on epidermal cell signaling, proliferation, and Skin inflammation in relation to their ability to inhibit Skin Tumor promotion by 12-O-tetradecanoylphorbol-13-acetate (TPA) and compared to UA as the prototype compound. All compounds were given topically 30 min prior to each TPA application and significantly inhibited Skin Tumor promotion. 3-epiCA and MA were significantly more effective than UA at inhibiting Tumor development. All of these compounds significantly inhibited epidermal proliferation induced by TPA, however, CA, 3-epiCA and MA were more effective than UA. All compounds also reduced Skin inflammation (assessed by infiltration of mast cells and T-cells) and inflammatory gene expression induced by TPA, however, 3-epiCA and MA were again more effective than UA. The greater ability of 3-epiCA and MA to inhibit Skin Tumor promotion was associated with greater reduction of Cox-2 and Twist1 proteins and inhibition of activation (i.e., phosphorylation) of IGF-1R, STAT3 and Src. Further study of these compounds, especially 3-epiCA and MA, for chemopreventive activity in other cancer model systems is warranted.
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abstract 1899 anti Skin Tumor promoting effects of pentacyclic triterpenes found in perilla frutescens
Cancer Research, 2015Co-Authors: Jiyoon Cho, Thomas J. Slaga, Okkyung Rho, Andrew M Camelio, Dionicio Siegel, Jacob J Junco, John DigiovanniAbstract:Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA In this study, we conducted a comprehensive examination of a series of pentacyclic tritperpenes found in P. frutescens, including ursolic acid (UA) oleanolic acid (OA), augustic acid (AA), corosolic acid (CA), 3-epi-corosolic acid (3-epiCA), maslinic acid (MA), and 3-epi-maslinic acid (3-epiMA) for their effects on epidermal cell signaling, proliferation, and Skin inflammation in relation to their ability to inhibit Skin Tumor promotion by TPA. For these experiments, female ICR mice (7-9 weeks of age) were treated with either acetone or 2 μmol of UA, OA, AA, CA, 3-epiCA, MA, or 3-epiMA 30 min prior to TPA (6.8 nmol) treatment The treatment protocol involved twice weekly treatments over a two week period. Mouse epidermis (6 hr time point) and whole Skin (48 hr time point) were collected for Western blot analysis and histological analysis, respectively. Pretreatment with these compounds inhibited the activation of JNK1/2, Src, and Stat3 as well as the induction of Cox-2 protein. Pretreatment with the compounds also reversed the effect of TPA on PDCD4 and p27, and increased the activation of AMPK and LKB1. We also examined the effect of the compounds on TPA-induced epidermal hyperproliferation as assessed by epidermal thickness and epidermal labeling index (LI). All of the compounds examined significantly inhibited TPA-induced epidermal hyperproliferation (significant reductions in both epidermal thickness and LI). In addition, the effect of the triterpenes on TPA-induced infiltration of mast cells in dermis was evaluated. UA significantly inhibited the infiltration of dermal mast cells induced by TPA. Notably, OA, AA, CA, 3-epiCA, MA, and 3-epiMA produced a greater inhibitory effect than that seen with UA on the number of infiltrated mast cells. Thus, UA and a series of related triterpenes differentially inhibited multiple signaling pathways, epidermal hyperproliferation, and a marker of Skin inflammation (infiltrated mast cells) induced by TPA. Several of the compounds including CA, 3-epiCA, MA, and 3-epiMA were particularly effective in these experiments. We are currently testing the ability of this group of compounds to inhibit Skin Tumor promotion by TPA in a two-stage Skin carcinogenesis experiment. Collectively, the current data suggest that several pentacyclic triterpenes, in addition to UA, may have potent chemopreventive activity. Research supported by CA164159. Citation Format: Jiyoon Cho, Okkyung Rho, Jacob Junco, Thomas J. Slaga, Andrew M. Camelio, Dionicio Siegel, John DiGiovanni. Anti-Skin Tumor promoting effects of pentacyclic triterpenes found in Perilla frutescens. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1899. doi:10.1158/1538-7445.AM2015-1899
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A novel mechanism of Skin Tumor promotion involving interferon‐gamma (IFNγ)/signal transducer and activator of transcription‐1 (Stat1) signaling
Molecular carcinogenesis, 2014Co-Authors: Ronald Bozeman, Linda M Beltran, Erika L. Abel, Everardo Macias, Tianyi Cheng, John DigiovanniAbstract:The current study was designed to explore the role of signal transducer and activator of transcription 1 (Stat1) during Tumor promotion using the mouse Skin multistage carcinogenesis model. Topical treatment with both 12-O-tetradecanoylphorbol-13-acetate (TPA) and 3-methyl-1,8-dihydroxy-9-anthrone (chrysarobin or CHRY) led to rapid phosphorylation of Stat1 on both tyrosine (Y701) and serine (S727) residues in epidermis. CHRY treatment also led to upregulation of unphosphorylated Stat1 (uStat1) at later time points. CHRY treatment also led to upregulation of interferon regulatory factor 1 (IRF-1) mRNA and protein, which was dependent on Stat1. Further analyses demonstrated that topical treatment with CHRY but not TPA upregulated interferon-gamma (IFNγ) mRNA in the epidermis and that the induction of both IRF-1 and uStat1 was dependent on IFNγ signaling. Stat1 deficient (Stat1−/−) mice were highly resistant to Skin Tumor promotion by CHRY. In contrast, the Tumor response (in terms of both papillomas and squamous cell carcinomas) was similar in Stat1−/− mice and wild-type littermates with TPA as the promoter. Maximal induction of both cyclooxygenase-2 and inducible nitric oxide synthase in epidermis following treatment with CHRY was also dependent on the presence of functional Stat1. These studies define a novel mechanism associated with Skin Tumor promotion by the anthrone class of Tumor promoters involving upregulation of IFNγ signaling in the epidermis and downstream signaling through activated (phosphorylated) Stat1, IRF-1 and uStat1. © 2014 Wiley Periodicals, Inc.
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Abstract 2556: Stat1 plays a major role in Skin Tumor promotion by chrysarobin but not TPA
Carcinogenesis, 2012Co-Authors: Ronald Bozeman, John DigiovanniAbstract:The cellular and molecular mechanisms that underlie promotion by diverse Tumor promoting agents remain to be fully elucidated. Studies using Stat1 knockout (KO) mice have shown that they were highly resistant to two-stage Skin carcinogenesis using chrysarobin as the promoter. In contrast, Stat1 KO mice treated with 12-O-tetradecanoylphorbol 13-acetate (TPA) as the Tumor promoter exhibited no significant differences in Tumor formation. To further investigate mechanism(s) whereby Stat1 mediates Skin Tumor promotion by chrysarobin Stat1 KO mice and wild-type (WT) controls were treated with the respective Tumor promoters and Stat1-dependent signaling pathways were evaluated. Mice deficient in Stat1 displayed an attenuated induction of epidermal Cox-2 mRNA and protein as well as reduced PGE2 levels compared to WT controls following topical application of chrysarobin, whereas, mice treated with TPA exhibited no significant differences in Cox-2 levels or PGE2 levels. Other results also suggest that Stat1 may regulate various cytokine/chemokines involved in the inflammatory response following chrysarobin treatment. Preliminary experiments have also shown that Stat1 KO mice exhibit reduced induction of interferon regulatory factor-1 (IRF-1) following chrysarobin treatment, compared to WT controls. In contrast, treatment with TPA caused no significant differences in expression of IRF-1. Collectively, these findings suggest that chrysarobin may elicit a Stat1-dependent signaling response that is dependent on IRF-1, whereas TPA-mediated Tumorigenesis is independent of this signaling pathway. These and other ongoing studies aimed at characterizing the role of Stat1 and IRF-1 signaling in chrysarobin-mediated Tumor promotion will be presented. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2556. doi:1538-7445.AM2012-2556
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Abstract 2730: Role of Stat1 in Skin Tumor promotion
Carcinogenesis, 2011Co-Authors: Ronald Bozeman, John Digiovanni, Erika L. AbelAbstract:Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Inflammation is a key component of cancer development in many tissues. Emerging clinical observations support the idea of a strong association of chronic inflammation and cancer. The JAK-STAT pathway is one of the major signaling pathways involved in modulating both pro- and anti-inflammatory responses. Aberrant expression of STATs has been reported in multiple human cancers and in animal models of Tumorigenesis. Previous work performed in our lab demonstrated a role for Stat1 in mediating the promotion stage of epithelial multi-stage carcinogenesis in mouse Skin when chrysarobin was used as the promoting agent. To further investigate the role of Stat1 in chrysarobin-mediated Skin Tumor promotion, Stat1 knockout (KO) mice and wild-type controls were treated with chrysarobin and the inflammatory response was assessed. Stat1 deficiency caused a reduction in the dermal inflammatory response following a single topical application of chrysarobin. In this regard, Stat1 KO mice had reduced dermal immune cell influx following chrysarobin treatment. In particular, Stat1 KO mice exhibited reduced influx of macrophages following a single application. Other results also suggest that Stat1 may regulate various cytokine/chemokines involved in the inflammatory response following chrysarobin treatment. Mice deficient in Stat1 displayed an attenuated induction of Cox-2 mRNA and protein compared to wild-type controls following a single application of chrysarobin (200 nmol per mouse). This latter data suggest that Stat1 may be involved in the regulation of Cox-2 in keratinocytes. Collectively, these findings suggest that Stat1 may contribute to chrysarobin-mediated Skin Tumor promotion by regulating, in part, levels of Cox-2, PGE2 and ultimately Skin inflammation. These and other ongoing studies aimed at identifying the mechanistic basis for the role of Stat1 in chrysarobin-mediated Tumor promotion will be presented. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2730. doi:10.1158/1538-7445.AM2011-2730
Linda M Beltran - One of the best experts on this subject based on the ideXlab platform.
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A novel mechanism of Skin Tumor promotion involving interferon‐gamma (IFNγ)/signal transducer and activator of transcription‐1 (Stat1) signaling
Molecular carcinogenesis, 2014Co-Authors: Ronald Bozeman, Linda M Beltran, Erika L. Abel, Everardo Macias, Tianyi Cheng, John DigiovanniAbstract:The current study was designed to explore the role of signal transducer and activator of transcription 1 (Stat1) during Tumor promotion using the mouse Skin multistage carcinogenesis model. Topical treatment with both 12-O-tetradecanoylphorbol-13-acetate (TPA) and 3-methyl-1,8-dihydroxy-9-anthrone (chrysarobin or CHRY) led to rapid phosphorylation of Stat1 on both tyrosine (Y701) and serine (S727) residues in epidermis. CHRY treatment also led to upregulation of unphosphorylated Stat1 (uStat1) at later time points. CHRY treatment also led to upregulation of interferon regulatory factor 1 (IRF-1) mRNA and protein, which was dependent on Stat1. Further analyses demonstrated that topical treatment with CHRY but not TPA upregulated interferon-gamma (IFNγ) mRNA in the epidermis and that the induction of both IRF-1 and uStat1 was dependent on IFNγ signaling. Stat1 deficient (Stat1−/−) mice were highly resistant to Skin Tumor promotion by CHRY. In contrast, the Tumor response (in terms of both papillomas and squamous cell carcinomas) was similar in Stat1−/− mice and wild-type littermates with TPA as the promoter. Maximal induction of both cyclooxygenase-2 and inducible nitric oxide synthase in epidermis following treatment with CHRY was also dependent on the presence of functional Stat1. These studies define a novel mechanism associated with Skin Tumor promotion by the anthrone class of Tumor promoters involving upregulation of IFNγ signaling in the epidermis and downstream signaling through activated (phosphorylated) Stat1, IRF-1 and uStat1. © 2014 Wiley Periodicals, Inc.
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Activation of epidermal akt by diverse mouse Skin Tumor promoters.
Molecular cancer research : MCR, 2007Co-Authors: Okkyung Rho, Linda M Beltran, Erik Wilker, John DigiovanniAbstract:Akt is a serine/threonine kinase involved in a variety of cellular responses, including cell proliferation and cell survival. Recent studies from our laboratory suggest that Akt signaling may play an important role in Skin Tumor promotion. To explore this premise, we examined epidermal Akt activation and signaling in response to chemically diverse Skin Tumor promoters. Mice received single or multiple applications of 12-O-tetradecanoylphorbol-13-acetate (TPA), okadaic acid, or chrysarobin. All three Tumor promoters were able to activate epidermal Akt as early as 1 h after treatment. Activation of Akt following Tumor promoter treatment led to enhanced downstream signaling, including hyperphosphorylation of glycogen synthase kinase-3beta and Bad. Structure activity studies with phorbol ester analogues revealed that the magnitude of activation paralleled Tumor-promoting activity. In cultured primary keratinocytes, TPA treatment also led to activation of Akt. Activation of the epidermal growth factor receptor (EGFR) seemed to underlie the ability of TPA to activate Akt as both PD153035, an inhibitor of EGFR, and GW2974, a dual-specific inhibitor of both EGFR and erbB2, were able to effectively reduce TPA-induced Akt phosphorylation as well as TPA-stimulated EGFR and erbB2 tyrosine phosphorylation in a dose-dependent manner. Furthermore, inhibition of protein kinase C (PKC) activity blocked TPA-stimulated heparin-binding EGF production and EGFR transactivation. Inhibition of PKC also led to a decreased association of Akt with the PP2A catalytic subunit, leading to increased Akt phosphorylation. However, combination of EGFR inhibitor and PKC inhibitor completely abrogated TPA-induced activation of Akt. Collectively, the current results support the hypothesis that elevated Akt activity and subsequent activation of downstream signaling pathways contribute significantly to Skin Tumor promotion. In addition, signaling through the EGFR via EGFR homodimers or EGFR/erbB2 heterodimers may be the primary event leading to Akt activation during Tumor promotion in mouse Skin.
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Enhancement of susceptibility to diverse Skin Tumor promoters by activation of the insulin-like growth factor-1 receptor in the epidermis of transgenic mice.
Molecular carcinogenesis, 1999Co-Authors: Erik Wilker, Linda M Beltran, Kaoru Kiguchi, Tim Rupp, David Bol, John DigiovanniAbstract:Insulin-like growth factor-1 (IGF-1) and its receptor are believed to play an important role in mitogenesis and neoplastic transformation. The purpose of this study was to further examine the role of IGF-1 during Tumor promotion in mouse Skin. HK1.IGF1 transgenic mice, which overexpress IGF-1 in epidermis via the human keratin 1 promoter, were previously shown to be hypersensitive to Skin Tumor promotion by 12-O-tetradecanoylphorbol-13-acetate (TPA). We examined these mice for their sensitivity to diverse classes of Tumor-promoting agents. HK1.IGF-1 transgenic mice initiated with 7,12-dimethylbenz[a]anthracene were more sensitive to treatment with a wide variety of Tumor promoters, including chrysarobin, okadaic acid, and benzoyl peroxide, which resulted in more rapid development of Tumors and a dramatic increase in the number of Tumors per mouse compared with corresponding non-transgenic mice treated with the same compounds. Histological analyses of Skin from HK1.IGF-1 mice treated with various Tumor promoters revealed that these mice were also more sensitive to the induction of epidermal hyperplasia and cell proliferation. Analysis of the IGF-1 receptor (IGF-1r) and epidermal growth factor (EGFr) in the epidermis of TPA-treated HK1.IGF-1 transgenic and non-transgenic mice revealed that both receptors were activated (hyperphosphorylated on tyrosine residues), and the level of activation was higher in transgenic mice. The mechanism for the increased sensitivity of HK1.IGF-1 mice to Tumor promoters may involve cooperation between the IGF-1r and EGFr signaling pathways. Our data suggest that IGF-1r signaling may play an important role in the process of Tumor promotion by diverse classes of Tumor promoters.
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comparison of 12 o tetradecanoylphorbol 13 acetate and teleocidin for induction of epidermal hyperplasia activation of epidermal pkc isozymes and Skin Tumor promotion in sencar and c57bl 6 mice
Carcinogenesis, 1993Co-Authors: Akira Imamoto, Hirota Fujiki, Susan E Walker, Linda M Beltran, Xiao-jing Wang, John DigiovanniAbstract:: The present study compared the ability of 12-O-tetradecanoylphorbol-13-acetate (TPA) and teleocidin to induce sustained epidermal hyperplasia, activate partially purified epidermal protein kinase C (PKC) isozymes and promote Skin Tumors in SENCAR and C57BL/6 mice. Teleocidin was less effective than TPA on a molar basis for inducing sustained epidermal hyperplasia, promoting Skin Tumors and activating partially purified epidermal PKC isozymes in vitro when examined using SENCAR mice. In contrast, teleocidin was more effective than TPA on a molar basis for inducing sustained epidermal hyperplasia, approximately equi-effective for promoting Skin Tumors and significantly less effective for activating PKC isozymes in vitro when examined using C57BL/6 mice. Despite the differences in response of C57BL/6 mice to TPA and teleocidin, this mouse strain was still highly resistant to Skin Tumor promotion by both types of promoters when compared with SENCAR mice. The current results, when considered in light of our recent studies (Cancer Res., 51, 1398-1405, 1991), indicate that C57BL/6 are generally resistant to a variety of classes of Skin Tumor promoters, including the teleocidins. In addition, except for the phorbol esters, the induction of sustained epidermal hyperplasia does not appear to be as good a marker for overall promotion responsiveness between SENCAR and C57BL/6 mice with other classes of Tumor promoters; although the induction of a significant sustained hyperplasia in the latter mouse strain did yield a weak Tumor response. Taken together, the current data suggest that factors in addition to the induction of sustained epidermal hyperplasia, control responsiveness of C57BL/6 mice to Skin Tumor promotion by diverse promoting stimuli.
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comparison of 12 o tetradecanoylphorbol 13 acetate and teleocidin for induction of epidermal hyperplasia activation of epidermal pkc isozymes and Skin Tumor promotion in sencar and c57bl 6 mice
Carcinogenesis, 1993Co-Authors: Akira Imamoto, Hirota Fujiki, Susan E Walker, Linda M Beltran, Xiao-jing Wang, John DigiovanniAbstract:: The present study compared the ability of 12-O-tetradecanoylphorbol-13-acetate (TPA) and teleocidin to induce sustained epidermal hyperplasia, activate partially purified epidermal protein kinase C (PKC) isozymes and promote Skin Tumors in SENCAR and C57BL/6 mice. Teleocidin was less effective than TPA on a molar basis for inducing sustained epidermal hyperplasia, promoting Skin Tumors and activating partially purified epidermal PKC isozymes in vitro when examined using SENCAR mice. In contrast, teleocidin was more effective than TPA on a molar basis for inducing sustained epidermal hyperplasia, approximately equi-effective for promoting Skin Tumors and significantly less effective for activating PKC isozymes in vitro when examined using C57BL/6 mice. Despite the differences in response of C57BL/6 mice to TPA and teleocidin, this mouse strain was still highly resistant to Skin Tumor promotion by both types of promoters when compared with SENCAR mice. The current results, when considered in light of our recent studies (Cancer Res., 51, 1398-1405, 1991), indicate that C57BL/6 are generally resistant to a variety of classes of Skin Tumor promoters, including the teleocidins. In addition, except for the phorbol esters, the induction of sustained epidermal hyperplasia does not appear to be as good a marker for overall promotion responsiveness between SENCAR and C57BL/6 mice with other classes of Tumor promoters; although the induction of a significant sustained hyperplasia in the latter mouse strain did yield a weak Tumor response. Taken together, the current data suggest that factors in addition to the induction of sustained epidermal hyperplasia, control responsiveness of C57BL/6 mice to Skin Tumor promotion by diverse promoting stimuli.
Thomas J. Slaga - One of the best experts on this subject based on the ideXlab platform.
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evaluation of pentacyclic triterpenes found in perilla frutescens for inhibition of Skin Tumor promotion by 12 o tetradecanoylphorbol 13 acetate
Oncotarget, 2015Co-Authors: Jiyoon Cho, Thomas J. Slaga, Okkyung Rho, Lisa Tremmel, Andrew M Camelio, Dionicio Siegel, John DigiovanniAbstract:A series of pentacyclic tritperpenes found in Perilla frutescens (P. frutescens), including ursolic acid (UA), oleanolic acid (OA), corosolic acid (CA), 3-epi-corosolic acid (3-epiCA), maslinic acid (MA), and 3-epi-maslinic acid (3-epiMA) were evaluated for their effects on epidermal cell signaling, proliferation, and Skin inflammation in relation to their ability to inhibit Skin Tumor promotion by 12-O-tetradecanoylphorbol-13-acetate (TPA) and compared to UA as the prototype compound. All compounds were given topically 30 min prior to each TPA application and significantly inhibited Skin Tumor promotion. 3-epiCA and MA were significantly more effective than UA at inhibiting Tumor development. All of these compounds significantly inhibited epidermal proliferation induced by TPA, however, CA, 3-epiCA and MA were more effective than UA. All compounds also reduced Skin inflammation (assessed by infiltration of mast cells and T-cells) and inflammatory gene expression induced by TPA, however, 3-epiCA and MA were again more effective than UA. The greater ability of 3-epiCA and MA to inhibit Skin Tumor promotion was associated with greater reduction of Cox-2 and Twist1 proteins and inhibition of activation (i.e., phosphorylation) of IGF-1R, STAT3 and Src. Further study of these compounds, especially 3-epiCA and MA, for chemopreventive activity in other cancer model systems is warranted.
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abstract 1899 anti Skin Tumor promoting effects of pentacyclic triterpenes found in perilla frutescens
Cancer Research, 2015Co-Authors: Jiyoon Cho, Thomas J. Slaga, Okkyung Rho, Andrew M Camelio, Dionicio Siegel, Jacob J Junco, John DigiovanniAbstract:Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA In this study, we conducted a comprehensive examination of a series of pentacyclic tritperpenes found in P. frutescens, including ursolic acid (UA) oleanolic acid (OA), augustic acid (AA), corosolic acid (CA), 3-epi-corosolic acid (3-epiCA), maslinic acid (MA), and 3-epi-maslinic acid (3-epiMA) for their effects on epidermal cell signaling, proliferation, and Skin inflammation in relation to their ability to inhibit Skin Tumor promotion by TPA. For these experiments, female ICR mice (7-9 weeks of age) were treated with either acetone or 2 μmol of UA, OA, AA, CA, 3-epiCA, MA, or 3-epiMA 30 min prior to TPA (6.8 nmol) treatment The treatment protocol involved twice weekly treatments over a two week period. Mouse epidermis (6 hr time point) and whole Skin (48 hr time point) were collected for Western blot analysis and histological analysis, respectively. Pretreatment with these compounds inhibited the activation of JNK1/2, Src, and Stat3 as well as the induction of Cox-2 protein. Pretreatment with the compounds also reversed the effect of TPA on PDCD4 and p27, and increased the activation of AMPK and LKB1. We also examined the effect of the compounds on TPA-induced epidermal hyperproliferation as assessed by epidermal thickness and epidermal labeling index (LI). All of the compounds examined significantly inhibited TPA-induced epidermal hyperproliferation (significant reductions in both epidermal thickness and LI). In addition, the effect of the triterpenes on TPA-induced infiltration of mast cells in dermis was evaluated. UA significantly inhibited the infiltration of dermal mast cells induced by TPA. Notably, OA, AA, CA, 3-epiCA, MA, and 3-epiMA produced a greater inhibitory effect than that seen with UA on the number of infiltrated mast cells. Thus, UA and a series of related triterpenes differentially inhibited multiple signaling pathways, epidermal hyperproliferation, and a marker of Skin inflammation (infiltrated mast cells) induced by TPA. Several of the compounds including CA, 3-epiCA, MA, and 3-epiMA were particularly effective in these experiments. We are currently testing the ability of this group of compounds to inhibit Skin Tumor promotion by TPA in a two-stage Skin carcinogenesis experiment. Collectively, the current data suggest that several pentacyclic triterpenes, in addition to UA, may have potent chemopreventive activity. Research supported by CA164159. Citation Format: Jiyoon Cho, Okkyung Rho, Jacob Junco, Thomas J. Slaga, Andrew M. Camelio, Dionicio Siegel, John DiGiovanni. Anti-Skin Tumor promoting effects of pentacyclic triterpenes found in Perilla frutescens. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1899. doi:10.1158/1538-7445.AM2015-1899
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The effects of dissociated glucocorticoids RU24858 and RU24782 on TPA-induced Skin Tumor promotion biomarkers in SENCAR mice.
Molecular carcinogenesis, 2013Co-Authors: Piotr Kowalczyk, Jacob Junco, Magdalena C. Kowalczyk, Renata Sosnowska, Olga Tolstykh, Zbigniew Walaszek, Margaret Hanausek, Thomas J. SlagaAbstract:Glucocorticoids (GCs) are very effective at preventing carcinogen- and Tumor promoter-induced Skin inflammation, hyperplasia, and mouse Skin Tumor formation. The effects of GCs are mediated by a well-known transcription factor, the glucocorticoid receptor (GR). GR acts via two different mechanisms: transcriptional regulation that requires DNA-binding (transactivation) and DNA binding-independent protein-protein interactions between GR and other transcription factors, such as nuclear factor kappa B (NF-κB) or activator protein 1 (AP-1; transrepression). We hypothesize that the transrepression activities of the GR are sufficient to suppress Skin Tumor promotion. We obtained two GCs (RU24858 and RU24782) that have dissociated downstream effects and induce only transrepression activities of the GR in a number of systems. These compounds bind the GR with high affinity and repress AP-1 and NF-κB activities while showing a lack of GR transactivation. RU24858, RU24782, or control full GCs desoximetasone (DES) and fluocinolone acetonide (FA) were applied to the dorsal Skin of SENCAR mice prior to application of the Tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA), two times per week for 2 weeks. DES, FA and RU24858 reversed TPA-induced epidermal hyperplasia and proliferation, while RU24782 treatment had no effect on these markers of Skin Tumor promotion. All tested compounds decreased TPA-induced c-jun mRNA levels in Skin. DES, FA, and RU24858, but not RU24782, were also able to reverse TPA-induced increases in the mRNA levels of COX-2 and iNOS. These findings show that RU24858 but not RU24782 reduced TPA-induced epidermal hyperplasia, proliferation, and inflammation, while both compounds reversed c-jun mRNA increases in the Skin.
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comparison of the Skin Tumor promoting potential of different organic peroxides in sencar mice
Toxicology and Applied Pharmacology, 1998Co-Authors: Irma B Gimenezconti, R L Binder, Dennis A. Johnston, Thomas J. SlagaAbstract:The Skin Tumor-promoting activities of three organic peroxides were evaluated and compared to the activity of benzoyl peroxide, a well-characterized Tumor promoter. Two of the compounds (di-t-butyl peroxide and dicumyl peroxide) were dialkyl peroxides and the other (di-m-chlorobenzoyl peroxide) was a diacyl peroxide. These compounds were selected based on a previous study in which we evaluated their capacity to induce epidermal hyperplasia, ornithine decarboxylase activity, and dark basal keratinocytes, which have been reliable short-term markers of Tumor promotion. Dicumyl peroxide was a weak Tumor promoter despite its high activity in inducing hyperplasia. Like benzoyl peroxide, di-m-chlorobenzoyl peroxide generally had intermediate activity as an inducer of short-term markers of Tumor promotion and was a moderately effective Tumor promoter. However, compared to benzoyl peroxide, di-m-chlorobenzoyl peroxide was more toxic to the Skin, which may have limited its Tumor-promoting activity. The final compound, di-t-butyl peroxide, which was essentially inactive in short-term assays, was also totally inactive in promoting papillomas or carcinomas in initiated Skin. Tumor-promoting efficacy generally showed an inverse association with thermal stability for the compounds tested, suggesting that the rate of formation of free radicals is a key factor contributing to Tumor promotion by organic peroxides. However, a number of other factors can potentially affect the activity of different organic peroxides as Tumor promoters. Each compound evaluated had a different spectrum of activities, and these compounds should be useful for studying mechanisms of organic peroxide-induced Tumor promotion.
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Inhibition of Skin Tumor initiation, promotion, and progression by antioxidants and related compounds
Critical reviews in food science and nutrition, 1995Co-Authors: Thomas J. SlagaAbstract:Abstract Antioxidants have been shown to inhibit the induction of cancer by a wide variety of chemical carcinogens and radiation at many target sites in mice, rats, hamsters, and man. Evidence is accumulating that suggests that free radicals are important in all stages of chemical carcinogenesis. Both carcinogens and Tumor promoters have also been shown to decrease the cellular activity of superoxide dismutase and catalase. A number of antioxidants and related compounds were tested to determine if they would inhibit either Skin Tumor initiation, promotion, or progression. In terms of Skin Tumor initiation, compounds such as BHT, vitamins E and C, and CuDIPS have been found to inhibit DMBA Skin Tumor initiation. The mechanism of action of these compounds appears to be related to their effect on the metabolism of DMBA, as BHT and CuDIPS do not inhibit the initiating activity of BP‐diol‐epoxide and MNNG. Although several antioxidants do inhibit Skin Tumor initiation by procarcinogens, antioxidants arc in gen...
Erika L. Abel - One of the best experts on this subject based on the ideXlab platform.
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A novel mechanism of Skin Tumor promotion involving interferon‐gamma (IFNγ)/signal transducer and activator of transcription‐1 (Stat1) signaling
Molecular carcinogenesis, 2014Co-Authors: Ronald Bozeman, Linda M Beltran, Erika L. Abel, Everardo Macias, Tianyi Cheng, John DigiovanniAbstract:The current study was designed to explore the role of signal transducer and activator of transcription 1 (Stat1) during Tumor promotion using the mouse Skin multistage carcinogenesis model. Topical treatment with both 12-O-tetradecanoylphorbol-13-acetate (TPA) and 3-methyl-1,8-dihydroxy-9-anthrone (chrysarobin or CHRY) led to rapid phosphorylation of Stat1 on both tyrosine (Y701) and serine (S727) residues in epidermis. CHRY treatment also led to upregulation of unphosphorylated Stat1 (uStat1) at later time points. CHRY treatment also led to upregulation of interferon regulatory factor 1 (IRF-1) mRNA and protein, which was dependent on Stat1. Further analyses demonstrated that topical treatment with CHRY but not TPA upregulated interferon-gamma (IFNγ) mRNA in the epidermis and that the induction of both IRF-1 and uStat1 was dependent on IFNγ signaling. Stat1 deficient (Stat1−/−) mice were highly resistant to Skin Tumor promotion by CHRY. In contrast, the Tumor response (in terms of both papillomas and squamous cell carcinomas) was similar in Stat1−/− mice and wild-type littermates with TPA as the promoter. Maximal induction of both cyclooxygenase-2 and inducible nitric oxide synthase in epidermis following treatment with CHRY was also dependent on the presence of functional Stat1. These studies define a novel mechanism associated with Skin Tumor promotion by the anthrone class of Tumor promoters involving upregulation of IFNγ signaling in the epidermis and downstream signaling through activated (phosphorylated) Stat1, IRF-1 and uStat1. © 2014 Wiley Periodicals, Inc.
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Proteomic and pathway analyses reveal a network of inflammatory genes associated with differences in Skin Tumor promotion susceptibility in DBA/2 and C57BL/6 mice.
Carcinogenesis, 2012Co-Authors: Jianjun Shen, Erika L. Abel, Penny K. Riggs, John Repass, Sean C. Hensley, Lisa J. Schroeder, Angelina Temple, Alexander Chau, S. Alex Mcclellan, Okkyung RhoAbstract:Genetic susceptibility to two-stage Skin carcinogenesis is known to vary significantly among different stocks and strains of mice. In an effort to identify specific protein changes or altered signaling pathways associated with Skin Tumor promotion susceptibility, a proteomic approach was used to examine and identify proteins that were differentially expressed in epidermis between promotion-sensitive DBA/2 and promotion-resistant C57BL/6 mice following treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA). We identified 19 differentially expressed proteins of which 5 were the calcium-binding proteins annexin A1, parvalbumin α, S100A8, S100A9, and S100A11. Further analyses revealed that S100A8 and S100A9 protein levels were also similarly differentially upregulated in epidermis of DBA/2 versus C57BL/6 mice following topical treatment with two other Skin Tumor promoters, okadaic acid and chrysarobin. Pathway analysis of all 19 identified proteins from the present study suggested that these proteins were components of several networks that included inflammation-associated proteins known to be involved in Skin Tumor promotion (e.g. TNF-α, NFκB). Follow-up studies revealed that Tnf, Nfkb1, Il22, Il1b, Cxcl1, Cxcl2 and Cxcl5 mRNAs were highly expressed in epidermis of DBA/2 compared with C57BL/6 mice at 24h following treatment with TPA. Furthermore, NFκB (p65) was also highly activated at the same time point (as measured by phosphorylation at ser276) in epidermis of DBA/2 mice compared with C57BL/6 mice. Taken together, the present data suggest that differential expression of genes involved in inflammatory pathways in epidermis may play a key role in genetic differences in susceptibility to Skin Tumor promotion in DBA/2 and C57BL/6 mice.
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Identification of a Network of Inflammatory Genes Associated with Differences in Skin Tumor Promotion Susceptibility
Journal of biomolecular techniques, 2012Co-Authors: Erika L. Abel, Penny K. Riggs, John Repass, Sean C. Hensley, Lisa J. Schroeder, Angelina Temple, Alexander Chau, S. Alex Mcclellan, Michael D. Ward, O. John SemmesAbstract:Genetic susceptibility to two-stage Skin carcinogenesis is known to vary significantly among different stocks and strains of mice. In an effort to identify specific protein changes or altered signaling pathways associated with Skin Tumor promotion susceptibility, a proteomic approach of two-dimensional (2-D) gel electrophoresis and mass spectrometry was used to examine and identify proteins that were differentially expressed in epidermis between promotion-sensitive DBA/2 and promotion-resistant C57BL/6 mice following treatment with the phorbol ester, 12-O-tetradecanoylphorbol-13-acetate. We identified 19 differentially expressed proteins of which 5 were the calcium-binding proteins including annexin A1, parvalbumin a, S100A8, S100A9, and S100A11. The differential expression of two of these calcium-binding proteins, S100A8 and S100A9, was further examined and validated by the following methods: i) one-dimensional (1-D) Western blot analysis; ii) 2-D Western blot analysis; iii) immunohistochemical analysis; and iv) quantitative real-time PCR. Further analyses revealed that S100A8 and S100A9 protein levels were also similarly differentially up-regulated in epidermis of DBA/2 vs C57BL/6 mice following topical treatment with two other Skin Tumor promoters, okadaic acid and chrysarobin. Pathway analysis of all 19 identified proteins from the present study suggested that these proteins were components of several networks that included inflammation associated proteins known to be involved in Skin Tumor promotion (e.g. TNF-a, NFkB). Follow-up studies revealed that Tnf, Nfkb1, Il22, and Il1a mRNAs were highly expressed in epidermis of TPA-treated DBA/2 (>2-fold, P
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Abstract 2730: Role of Stat1 in Skin Tumor promotion
Carcinogenesis, 2011Co-Authors: Ronald Bozeman, John Digiovanni, Erika L. AbelAbstract:Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Inflammation is a key component of cancer development in many tissues. Emerging clinical observations support the idea of a strong association of chronic inflammation and cancer. The JAK-STAT pathway is one of the major signaling pathways involved in modulating both pro- and anti-inflammatory responses. Aberrant expression of STATs has been reported in multiple human cancers and in animal models of Tumorigenesis. Previous work performed in our lab demonstrated a role for Stat1 in mediating the promotion stage of epithelial multi-stage carcinogenesis in mouse Skin when chrysarobin was used as the promoting agent. To further investigate the role of Stat1 in chrysarobin-mediated Skin Tumor promotion, Stat1 knockout (KO) mice and wild-type controls were treated with chrysarobin and the inflammatory response was assessed. Stat1 deficiency caused a reduction in the dermal inflammatory response following a single topical application of chrysarobin. In this regard, Stat1 KO mice had reduced dermal immune cell influx following chrysarobin treatment. In particular, Stat1 KO mice exhibited reduced influx of macrophages following a single application. Other results also suggest that Stat1 may regulate various cytokine/chemokines involved in the inflammatory response following chrysarobin treatment. Mice deficient in Stat1 displayed an attenuated induction of Cox-2 mRNA and protein compared to wild-type controls following a single application of chrysarobin (200 nmol per mouse). This latter data suggest that Stat1 may be involved in the regulation of Cox-2 in keratinocytes. Collectively, these findings suggest that Stat1 may contribute to chrysarobin-mediated Skin Tumor promotion by regulating, in part, levels of Cox-2, PGE2 and ultimately Skin inflammation. These and other ongoing studies aimed at identifying the mechanistic basis for the role of Stat1 in chrysarobin-mediated Tumor promotion will be presented. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2730. doi:10.1158/1538-7445.AM2011-2730
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Abstract 2729: Proteomic analysis reveals a network of inflammatory genes in epidermis associated with Skin Tumor promotion susceptibility in DBA/2 and C57BL/6 mice
Carcinogenesis, 2011Co-Authors: Jianjun Shen, Erika L. Abel, Penny K. Riggs, John Repass, Sean C. Hensley, Lisa J. Schroeder, Alexander Chau, Joe M. Angel, Angelina Traner, Michael D. WardAbstract:Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Genetic susceptibility to two-stage Skin carcinogenesis is known to vary significantly among different stocks and strains of mice. In an effort to identify specific protein changes or altered signaling pathways associated with Tumor promotion susceptibility by the phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA), a proteomic approach of two-dimensional (2-D) gel electrophoresis and mass spectrometry was used. In these experiments, we examined epidermal protein lysates and identified proteins that were differentially expressed in epidermis between promotion-sensitive DBA/2 and promotion-resistant C57BL/6 mice following TPA treatment. Among 19 differentially expressed proteins identified using this methodology were two calcium-binding proteins, S100A8 and S100A9. Their differential expression was further examined and validated by one or more of the following methods: i) one-dimensional (1-D) Western blot analysis; ii) 2-D Western blot analysis; iii) immunohistochemical analysis; and iv) quantitative real-time PCR. Further analyses revealed that S100A8 and S100A9 protein levels were also similarly differentially up-regulated in epidermis of DBA/2 vs C57BL/6 mice following topical treatment with two other Tumor promoters, okadaic acid and chrysarobin. Pathway analysis of all 19 identified proteins from the present study suggested that S100A8/A9 could be linked to several inflammatory networks. Further analyses revealed significantly increased expression of several inflammation-related genes including TNF-α, NFκB and IL-22 in epidermis of TPA-treated DBA/2 mice. Follow-up studies confirmed that these three inflammation related genes were upregulated in epidermis of TPA-treated DBA/2 mice compared to similarly treated C57BL/6 mice. These data suggest that differential expression of inflammation related genes in epidermis contributes to TPA-induced inflammation and Skin Tumor promotion susceptibility in DBA/2 mice. Taken together, our present data provide further insight into potential molecular mechanisms for the differential susceptibility of DBA/2 and C57BL/6 mice in terms of both inflammation and Skin Tumor promotion. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2729. doi:10.1158/1538-7445.AM2011-2729
Akira Imamoto - One of the best experts on this subject based on the ideXlab platform.
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Activation of the Epidermal Growth Factor Receptor by Skin Tumor Promoters and in Skin Tumors from SENCAR Mice
Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research, 1995Co-Authors: Wenjuan Xian, Akira Imamoto, Kaoru Kiguchi, Tim Rupp, A. Zilberstein, John DigiovanniAbstract:The present study was designed to further investigate the role of the epidermal growth factor receptor (EGFr) in mouse Skin Tumor promotion by evaluating the status of the EGFr in Tumor promoter-treated mouse epidermis and in mouse Skin Tumors. Female SENCAR mice received three topical treatments of either the phorbol ester 12-O-tetradecanoylphorbol-1 3-acetate (TPA) or the nonphorbol esters okadaic acid and chrysarobin. Membrane proteins from SENCAR mouse epidermis were isolated 6 h after the last treatment, and the phosphotyrosine content of the EGFr and several potential substrates were examined by Western blot analysis. The results indicated that multiple applications of all three Tumor promoters led to an increase in the phosphotyrosine content of the EGFr and also of several lower molecular weight proteins (Mr �8O,OOO85,OO0). Phosphorylation of PLCyl on tyrosine residues could not be detected in Tumor promoter-treated mouse epidermis when the phosphotyrosine content of the EGFr was elevated or in cultured keratinocytes exposed to exogenous [CF. When two tyrosine kinase inhibitors (tyrphostins RC50864 and RG1 3022) were incorporated into the treatment regimens, the TPA-induced epidermal hyperplasia and cell proliferation were effectively blocked, and the TPA-stimulated EGFr tyrosine phosphorylation was significantly reduced. Examination of the phosphotyrosine content of epidermal membrane proteins isolated from Skin papillomas revealed that the EGFr also had elevated phosphotyrosine levels. These results demonstrate that multiple topical treatments with both phorbol ester and nonphorbol ester Tumor promoters lead to activation of the EGFr tyrosine kinase in mouse epidermis. In addition, these data suggestthat signaling through the EGFr pathway plays an important role in the Tumor promotion stage of multistage carcinogenesis in mouse Skin.
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comparison of 12 o tetradecanoylphorbol 13 acetate and teleocidin for induction of epidermal hyperplasia activation of epidermal pkc isozymes and Skin Tumor promotion in sencar and c57bl 6 mice
Carcinogenesis, 1993Co-Authors: Akira Imamoto, Hirota Fujiki, Susan E Walker, Linda M Beltran, Xiao-jing Wang, John DigiovanniAbstract:: The present study compared the ability of 12-O-tetradecanoylphorbol-13-acetate (TPA) and teleocidin to induce sustained epidermal hyperplasia, activate partially purified epidermal protein kinase C (PKC) isozymes and promote Skin Tumors in SENCAR and C57BL/6 mice. Teleocidin was less effective than TPA on a molar basis for inducing sustained epidermal hyperplasia, promoting Skin Tumors and activating partially purified epidermal PKC isozymes in vitro when examined using SENCAR mice. In contrast, teleocidin was more effective than TPA on a molar basis for inducing sustained epidermal hyperplasia, approximately equi-effective for promoting Skin Tumors and significantly less effective for activating PKC isozymes in vitro when examined using C57BL/6 mice. Despite the differences in response of C57BL/6 mice to TPA and teleocidin, this mouse strain was still highly resistant to Skin Tumor promotion by both types of promoters when compared with SENCAR mice. The current results, when considered in light of our recent studies (Cancer Res., 51, 1398-1405, 1991), indicate that C57BL/6 are generally resistant to a variety of classes of Skin Tumor promoters, including the teleocidins. In addition, except for the phorbol esters, the induction of sustained epidermal hyperplasia does not appear to be as good a marker for overall promotion responsiveness between SENCAR and C57BL/6 mice with other classes of Tumor promoters; although the induction of a significant sustained hyperplasia in the latter mouse strain did yield a weak Tumor response. Taken together, the current data suggest that factors in addition to the induction of sustained epidermal hyperplasia, control responsiveness of C57BL/6 mice to Skin Tumor promotion by diverse promoting stimuli.
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comparison of 12 o tetradecanoylphorbol 13 acetate and teleocidin for induction of epidermal hyperplasia activation of epidermal pkc isozymes and Skin Tumor promotion in sencar and c57bl 6 mice
Carcinogenesis, 1993Co-Authors: Akira Imamoto, Hirota Fujiki, Susan E Walker, Linda M Beltran, Xiao-jing Wang, John DigiovanniAbstract:: The present study compared the ability of 12-O-tetradecanoylphorbol-13-acetate (TPA) and teleocidin to induce sustained epidermal hyperplasia, activate partially purified epidermal protein kinase C (PKC) isozymes and promote Skin Tumors in SENCAR and C57BL/6 mice. Teleocidin was less effective than TPA on a molar basis for inducing sustained epidermal hyperplasia, promoting Skin Tumors and activating partially purified epidermal PKC isozymes in vitro when examined using SENCAR mice. In contrast, teleocidin was more effective than TPA on a molar basis for inducing sustained epidermal hyperplasia, approximately equi-effective for promoting Skin Tumors and significantly less effective for activating PKC isozymes in vitro when examined using C57BL/6 mice. Despite the differences in response of C57BL/6 mice to TPA and teleocidin, this mouse strain was still highly resistant to Skin Tumor promotion by both types of promoters when compared with SENCAR mice. The current results, when considered in light of our recent studies (Cancer Res., 51, 1398-1405, 1991), indicate that C57BL/6 are generally resistant to a variety of classes of Skin Tumor promoters, including the teleocidins. In addition, except for the phorbol esters, the induction of sustained epidermal hyperplasia does not appear to be as good a marker for overall promotion responsiveness between SENCAR and C57BL/6 mice with other classes of Tumor promoters; although the induction of a significant sustained hyperplasia in the latter mouse strain did yield a weak Tumor response. Taken together, the current data suggest that factors in addition to the induction of sustained epidermal hyperplasia, control responsiveness of C57BL/6 mice to Skin Tumor promotion by diverse promoting stimuli.
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evidence for autocrine paracrine growth stimulation by transforming growth factor α during the process of Skin Tumor promotion
Molecular Carcinogenesis, 1991Co-Authors: Akira Imamoto, Linda M Beltran, John DigiovanniAbstract:: A single topical application of 12-O-tetradecanoylphorbol-13-acetate (TPA) to mouse Skin decreased 125I-labeled epidermal growth factor (EGF) binding in epidermal membrane preparations within 1 h while 1,8-dihydroxy-3-methyl-9-anthrone (chrysarobin) gradually reduced binding with maximum inhibition at 15 h. Subsequently, 125I-EGF binding increased to approximately 200% of control in epidermal membrane preparations from both TPA- and chrysarobin-treated mice. A single application of TPA but not chrysarobin resulted in a rapid translocation of protein kinase C (PKC) to the membrane; however, treatment with both promoters ultimately led to a time-dependent loss of PKC activity in both membrane and cytosol fractions. The initial inhibition of 125I-EGF binding was sustained for at least 24 h after single and multiple treatments with both promoting agents. Acid washing restored EGF binding to control levels in membrane preparations obtained 24 h after a single application, whereas acid washing of membrane preparations obtained 24 h after a second application of TPA or chrysarobin increased binding (2.5-fold and 1.5-fold that of the control, respectively). The presence of increased amounts of ligands for the EGF receptor in Tumor promoter-treated epidermis was initially confirmed in 125I-EGF binding competition experiments using NRK-49F cells. A single topical application of TPA or chrysarobin induced elevated levels of transforming growth factor-alpha (TGF-alpha) mRNA at 6 h or 15-24 h, respectively. Elevated levels of a TGF-alpha precursor (21 kDa) were subsequently observed in cytosol and membrane preparations after single and multiple applications of TPA or chrysarobin. These results suggest that repeated topical application of Tumor promoters may lead to sustained loss of a negative-feedback mechanism involving phosphorylation at Thr-654 of the EGF receptor by PKC. The concomitant elevation of ligands, such as TGF-alpha, may provide a mechanism for sustained cell proliferation essential for Skin Tumor promotion.
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Evidence for autocrine/paracrine growth stimulation by transforming growth factor‐α during the process of Skin Tumor promotion
Molecular carcinogenesis, 1991Co-Authors: Akira Imamoto, Linda M Beltran, John DigiovanniAbstract:A single topical application of 12-O-tetradecanoylphorbol-13-acetate (TPA) to mouse Skin decreased 125I-labeled epidermal growth factor (EGF) binding in epidermal membrane preparations within 1 h while 1,8-dihydroxy-3-methyl-9-anthrone (chrysarobin) gradually reduced binding with maximum inhibition at 15 h. Subsequently, 125I-EGF binding increased to approximately 200% of control in epidermal membrane preparations from both TPA- and chrysarobin-treated mice. A single application of TPA but not chrysarobin resulted in a rapid translocation of protein kinase C (PKC) to the membrane; however, treatment with both promoters ultimately led to a time-dependent loss of PKC activity in both membrane and cytosol fractions. The initial inhibition of 125I-EGF binding was sustained for at least 24 h after single and multiple treatments with both promoting agents. Acid washing restored EGF binding to control levels in membrane preparations obtained 24 h after a single application, whereas acid washing of membrane preparations obtained 24 h after a second application of TPA or chrysarobin increased binding (2.5-fold and 1.5-fold that of the control, respectively). The presence of increased amounts of ligands for the EGF receptor in Tumor promoter-treated epidermis was initially confirmed in 125I-EGF binding competition experiments using NRK-49F cells. A single topical application of TPA or chrysarobin induced elevated levels of transforming growth factor-alpha (TGF-alpha) mRNA at 6 h or 15-24 h, respectively. Elevated levels of a TGF-alpha precursor (21 kDa) were subsequently observed in cytosol and membrane preparations after single and multiple applications of TPA or chrysarobin. These results suggest that repeated topical application of Tumor promoters may lead to sustained loss of a negative-feedback mechanism involving phosphorylation at Thr-654 of the EGF receptor by PKC. The concomitant elevation of ligands, such as TGF-alpha, may provide a mechanism for sustained cell proliferation essential for Skin Tumor promotion.
