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Kuenfeng Chen - One of the best experts on this subject based on the ideXlab platform.

  • abstract 3803 obatoclax analogue sc 2001 inhibits stat3 phosphorylation by enhancing protein tyrosine phosphatase shp 1 expression and induces apoptosis in human breast cancer cells
    Cancer Research, 2014
    Co-Authors: Chunyu Liu, Chungwai Shiau, Ling-ming Tseng, Peiyi Chu, Weitien Tai, Kuenfeng Chen
    Abstract:

    Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Background: Interfering the oncogenic STAT3 signaling is considered as promising anti-cancer strategy. Previously, we have reported an obatoclax analogue, SC-2001, as a novel STAT3 inhibitor in hepatocellular carcinoma cells (Cancer Letter 2012). Here, we examined the efficacy and Drug Mechanism of SC-2001 in breast cancer cells. Methods: Human breast cancer cell lines were used for in vitro studies. Cell viability was examined by MTT assay. Apoptosis was examined by both flow cytometry and western blot. Signal transduction pathways in cells were assessed by western blot. Small interference RNA was used to knockdown SHP-1. Quantitative RT-PCR was used for assessing gene transcription. In vivo efficacy of SC-2001 was tested in xenografted nude mice. Results: SC-2001 inhibited cell growth and induced apoptosis in breast cancer cell lines (MDA-MB-468, MDA-MB-231, MDA-MB-453, MCF-7 and HCC 1937). SC-2001 downregulated the phosphorylation of STAT3 (Tyr 705) and subsequently inhibited its transcriptional activities in a dose-dependent manner. STAT3-regulated proteins, including Mcl-1, survivin and cyclin D1, were also repressed by SC-2001. Over-expression of STAT3 in MDA-MB-468 cells protected cells from SC-2001-induced apoptosis. Moreover, SC-2001 enhanced the expression of SHP-1, a negative regulator of STAT3, in a time-dependent manner. The enhanced SHP-1 expression, in conjunction with increased SHP-1 phosphatase activity, was mediated by upregulated transcription. Furthermore, co-immunoprecipitation experiment showed that SC-2001 upregulated SHP-1 expression through enhanced transcription by RFX-1 transcription factor. Importantly, SC-2001 showed efficacious antitumor activity and p-STAT3 downregulation in MDA-MB-468 xenograft tumors. Conclusion: Our results suggest that SC-2001 induced apoptosis in breast cancer cells, and that this effect is mediated through RFX-1 upregulated SHP-1 expression and SHP-1-dependent STAT3 inactivation. (Supported by Yen Tjing Ling Medical Foundation; NSC 101-2325-B-075-006, NSC-102-2325-B-075-006 and NSC 100-2325-B-010-007; and V100-D-005-4) Citation Format: Chun-Yu Liu, Jung-Chen Su, Ling-Ming Tseng, Pei-Yi Chu, Wei-Tien Tai, Chung-Wai Shiau, Kuen-Feng Chen. Obatoclax analogue SC-2001 inhibits STAT3 phosphorylation by enhancing protein tyrosine phosphatase SHP-1 expression and induces apoptosis in human breast cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3803. doi:10.1158/1538-7445.AM2014-3803

  • Obatoclax analog SC-2001 inhibits STAT3 phosphorylation through enhancing SHP-1 expression and induces apoptosis in human breast cancer cells
    Breast Cancer Research and Treatment, 2014
    Co-Authors: Jung-chen Su, Chungwai Shiau, Mei-huei Ni, Ling-ming Tseng, Duen-shian Wang, Man-hsin Hung, Kuenfeng Chen
    Abstract:

    Interfering oncogenic STAT3 signaling is a promising anti-cancer strategy. We examined the efficacy and Drug Mechanism of an obatoclax analog SC-2001, a novel STAT3 inhibitor, in human breast cancer cells. Human breast cancer cell lines were used for in vitro studies. Apoptosis was examined by both flow cytometry and western blot. Signaling pathways were assessed by western blot. In vivo efficacy of SC-2001 was tested in xenograft nude mice. SC-2001 inhibited cell growth and induced apoptosis in association with downregulation of p-STAT3 (Tyr 705) in breast cancer cells. STAT3-regulated proteins, including Mcl-1, survivin, and cyclin D1, were repressed by SC-2001. Over-expression of STAT3 in MDA-MB-468 cells protected cells from SC-2001-induced apoptosis. Moreover, SC-2001 enhanced the expression of protein tyrosine phosphatase SHP-1, a negative regulator of STAT3. Furthermore, the enhanced SHP-1 expression, in conjunction with increased SHP-1 phosphatase activity, was mediated by upregulated transcription by RFX-1. Chromatin immunoprecipitation assay revealed that SC-2001 increased the binding capacity of RFX-1 to the SHP-1 promoter. Knockdown of either RFX-1 or SHP-1 reduced SC-2001-induced apoptosis, whereas ectopic expression of RFX-1 increased SHP-1 expression and enhanced the apoptotic effect of SC-2001. Importantly, SC-2001 suppressed tumor growth in association with enhanced RFX-1 and SHP-1 expression and p-STAT3 downregulation in MDA-MB-468 xenograft tumors. SC-2001 induced apoptosis in breast cancer cells, an effect that was mediated by RFX-1 upregulated SHP-1 expression and SHP-1-dependent STAT3 inactivation. Our study indicates targeting STAT3 signaling pathway may be a useful approach for the development of targeted agents for anti-breast cancer.

  • abstract 4515 a novel obatoclax derivative is a promising agent to overcome bortezomib s resistance in acute leukemia cells
    Cancer Research, 2011
    Co-Authors: Chunyu Liu, Chungwai Shiau, Hsinyu Kuo, Annlii Cheng, Chenghwai Tzeng, Kuenfeng Chen
    Abstract:

    Background: Our previous work showed that bortezomib, a reverse-inhibitor of the 26S proteasome, exerts differential cytotoxic effects to acute leukemia cells through down-regulation of phosphor-Akt (AACR 2010 abstract 1575). Interestingly, some acute leukemia cells (MOLT-3 and K562) are resistant to bortezomib. One of the resistant Mechanisms of bortezomib involves the abnormality in intrinsic apoptotic pathway members, the bcl-2 family. Of particular, it has been shown that bortezomib induces upregulation of Mcl-1 and that Mcl-1 accumulation may delay bortezomib-induced apoptosis. Obatoclax, a small molecule inhibitor of pro-survival BCL-2 members, including MCL-1, synergizes with bortezomib in mantle cell lymphoma (Blood 2007) and may overcome bortezomib resistance. Here, we designed a novel Mcl-1 inhibitor deriving from obatoclax, SC-2001, to overcome the resistance. Methods: MOLT-3 and K562 cell lines were used for in vitro studies. Apoptosis was examined by both flow cytometry and Western blot. Signal transduction pathways in cells were assessed by Western Blot. Gene silencing was done by small interference RNA (siRNA). Results: MOLT-3 and K562 were resistant to bortezomib up to 100nM. Upregulation of Mcl-1 expression after bortezomib treatment were evident in these cells. Interestingly, the addition of either obatoclax or SC-2001, restored the sensitivity of K562 and MOLT-3 cells to bortezomib. SC-2001, comparing to obatoclax, exerted better efficacy in sensitivity restoration of bortezomib in association with Mcl-1 downregulation in MOLT-3 cells. Moreover, down-regulation of Mcl-1 by siRNA overcame the apoptotic resistance to bortezomib in K562 cells. These data indicate that novel Mcl-1 inhibitors could restore bortezomib sensitivity in resistant acute leukemia cells. Conclusions: a novel Mcl-1 inhibitor SC-2001, is a promising agent to overcome bortezomib9s resistance in acute leukemia, further elucidating the Drug Mechanism regulating Mcl-1 inhibition is needed. Supported by VGHTPE 99DHA0100332 and 100DHA0100591 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 4515. doi:10.1158/1538-7445.AM2011-4515

Chungwai Shiau - One of the best experts on this subject based on the ideXlab platform.

  • abstract 3803 obatoclax analogue sc 2001 inhibits stat3 phosphorylation by enhancing protein tyrosine phosphatase shp 1 expression and induces apoptosis in human breast cancer cells
    Cancer Research, 2014
    Co-Authors: Chunyu Liu, Chungwai Shiau, Ling-ming Tseng, Peiyi Chu, Weitien Tai, Kuenfeng Chen
    Abstract:

    Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Background: Interfering the oncogenic STAT3 signaling is considered as promising anti-cancer strategy. Previously, we have reported an obatoclax analogue, SC-2001, as a novel STAT3 inhibitor in hepatocellular carcinoma cells (Cancer Letter 2012). Here, we examined the efficacy and Drug Mechanism of SC-2001 in breast cancer cells. Methods: Human breast cancer cell lines were used for in vitro studies. Cell viability was examined by MTT assay. Apoptosis was examined by both flow cytometry and western blot. Signal transduction pathways in cells were assessed by western blot. Small interference RNA was used to knockdown SHP-1. Quantitative RT-PCR was used for assessing gene transcription. In vivo efficacy of SC-2001 was tested in xenografted nude mice. Results: SC-2001 inhibited cell growth and induced apoptosis in breast cancer cell lines (MDA-MB-468, MDA-MB-231, MDA-MB-453, MCF-7 and HCC 1937). SC-2001 downregulated the phosphorylation of STAT3 (Tyr 705) and subsequently inhibited its transcriptional activities in a dose-dependent manner. STAT3-regulated proteins, including Mcl-1, survivin and cyclin D1, were also repressed by SC-2001. Over-expression of STAT3 in MDA-MB-468 cells protected cells from SC-2001-induced apoptosis. Moreover, SC-2001 enhanced the expression of SHP-1, a negative regulator of STAT3, in a time-dependent manner. The enhanced SHP-1 expression, in conjunction with increased SHP-1 phosphatase activity, was mediated by upregulated transcription. Furthermore, co-immunoprecipitation experiment showed that SC-2001 upregulated SHP-1 expression through enhanced transcription by RFX-1 transcription factor. Importantly, SC-2001 showed efficacious antitumor activity and p-STAT3 downregulation in MDA-MB-468 xenograft tumors. Conclusion: Our results suggest that SC-2001 induced apoptosis in breast cancer cells, and that this effect is mediated through RFX-1 upregulated SHP-1 expression and SHP-1-dependent STAT3 inactivation. (Supported by Yen Tjing Ling Medical Foundation; NSC 101-2325-B-075-006, NSC-102-2325-B-075-006 and NSC 100-2325-B-010-007; and V100-D-005-4) Citation Format: Chun-Yu Liu, Jung-Chen Su, Ling-Ming Tseng, Pei-Yi Chu, Wei-Tien Tai, Chung-Wai Shiau, Kuen-Feng Chen. Obatoclax analogue SC-2001 inhibits STAT3 phosphorylation by enhancing protein tyrosine phosphatase SHP-1 expression and induces apoptosis in human breast cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3803. doi:10.1158/1538-7445.AM2014-3803

  • Obatoclax analog SC-2001 inhibits STAT3 phosphorylation through enhancing SHP-1 expression and induces apoptosis in human breast cancer cells
    Breast Cancer Research and Treatment, 2014
    Co-Authors: Jung-chen Su, Chungwai Shiau, Mei-huei Ni, Ling-ming Tseng, Duen-shian Wang, Man-hsin Hung, Kuenfeng Chen
    Abstract:

    Interfering oncogenic STAT3 signaling is a promising anti-cancer strategy. We examined the efficacy and Drug Mechanism of an obatoclax analog SC-2001, a novel STAT3 inhibitor, in human breast cancer cells. Human breast cancer cell lines were used for in vitro studies. Apoptosis was examined by both flow cytometry and western blot. Signaling pathways were assessed by western blot. In vivo efficacy of SC-2001 was tested in xenograft nude mice. SC-2001 inhibited cell growth and induced apoptosis in association with downregulation of p-STAT3 (Tyr 705) in breast cancer cells. STAT3-regulated proteins, including Mcl-1, survivin, and cyclin D1, were repressed by SC-2001. Over-expression of STAT3 in MDA-MB-468 cells protected cells from SC-2001-induced apoptosis. Moreover, SC-2001 enhanced the expression of protein tyrosine phosphatase SHP-1, a negative regulator of STAT3. Furthermore, the enhanced SHP-1 expression, in conjunction with increased SHP-1 phosphatase activity, was mediated by upregulated transcription by RFX-1. Chromatin immunoprecipitation assay revealed that SC-2001 increased the binding capacity of RFX-1 to the SHP-1 promoter. Knockdown of either RFX-1 or SHP-1 reduced SC-2001-induced apoptosis, whereas ectopic expression of RFX-1 increased SHP-1 expression and enhanced the apoptotic effect of SC-2001. Importantly, SC-2001 suppressed tumor growth in association with enhanced RFX-1 and SHP-1 expression and p-STAT3 downregulation in MDA-MB-468 xenograft tumors. SC-2001 induced apoptosis in breast cancer cells, an effect that was mediated by RFX-1 upregulated SHP-1 expression and SHP-1-dependent STAT3 inactivation. Our study indicates targeting STAT3 signaling pathway may be a useful approach for the development of targeted agents for anti-breast cancer.

  • abstract 4515 a novel obatoclax derivative is a promising agent to overcome bortezomib s resistance in acute leukemia cells
    Cancer Research, 2011
    Co-Authors: Chunyu Liu, Chungwai Shiau, Hsinyu Kuo, Annlii Cheng, Chenghwai Tzeng, Kuenfeng Chen
    Abstract:

    Background: Our previous work showed that bortezomib, a reverse-inhibitor of the 26S proteasome, exerts differential cytotoxic effects to acute leukemia cells through down-regulation of phosphor-Akt (AACR 2010 abstract 1575). Interestingly, some acute leukemia cells (MOLT-3 and K562) are resistant to bortezomib. One of the resistant Mechanisms of bortezomib involves the abnormality in intrinsic apoptotic pathway members, the bcl-2 family. Of particular, it has been shown that bortezomib induces upregulation of Mcl-1 and that Mcl-1 accumulation may delay bortezomib-induced apoptosis. Obatoclax, a small molecule inhibitor of pro-survival BCL-2 members, including MCL-1, synergizes with bortezomib in mantle cell lymphoma (Blood 2007) and may overcome bortezomib resistance. Here, we designed a novel Mcl-1 inhibitor deriving from obatoclax, SC-2001, to overcome the resistance. Methods: MOLT-3 and K562 cell lines were used for in vitro studies. Apoptosis was examined by both flow cytometry and Western blot. Signal transduction pathways in cells were assessed by Western Blot. Gene silencing was done by small interference RNA (siRNA). Results: MOLT-3 and K562 were resistant to bortezomib up to 100nM. Upregulation of Mcl-1 expression after bortezomib treatment were evident in these cells. Interestingly, the addition of either obatoclax or SC-2001, restored the sensitivity of K562 and MOLT-3 cells to bortezomib. SC-2001, comparing to obatoclax, exerted better efficacy in sensitivity restoration of bortezomib in association with Mcl-1 downregulation in MOLT-3 cells. Moreover, down-regulation of Mcl-1 by siRNA overcame the apoptotic resistance to bortezomib in K562 cells. These data indicate that novel Mcl-1 inhibitors could restore bortezomib sensitivity in resistant acute leukemia cells. Conclusions: a novel Mcl-1 inhibitor SC-2001, is a promising agent to overcome bortezomib9s resistance in acute leukemia, further elucidating the Drug Mechanism regulating Mcl-1 inhibition is needed. Supported by VGHTPE 99DHA0100332 and 100DHA0100591 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 4515. doi:10.1158/1538-7445.AM2011-4515

Ling-ming Tseng - One of the best experts on this subject based on the ideXlab platform.

  • abstract 3803 obatoclax analogue sc 2001 inhibits stat3 phosphorylation by enhancing protein tyrosine phosphatase shp 1 expression and induces apoptosis in human breast cancer cells
    Cancer Research, 2014
    Co-Authors: Chunyu Liu, Chungwai Shiau, Ling-ming Tseng, Peiyi Chu, Weitien Tai, Kuenfeng Chen
    Abstract:

    Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Background: Interfering the oncogenic STAT3 signaling is considered as promising anti-cancer strategy. Previously, we have reported an obatoclax analogue, SC-2001, as a novel STAT3 inhibitor in hepatocellular carcinoma cells (Cancer Letter 2012). Here, we examined the efficacy and Drug Mechanism of SC-2001 in breast cancer cells. Methods: Human breast cancer cell lines were used for in vitro studies. Cell viability was examined by MTT assay. Apoptosis was examined by both flow cytometry and western blot. Signal transduction pathways in cells were assessed by western blot. Small interference RNA was used to knockdown SHP-1. Quantitative RT-PCR was used for assessing gene transcription. In vivo efficacy of SC-2001 was tested in xenografted nude mice. Results: SC-2001 inhibited cell growth and induced apoptosis in breast cancer cell lines (MDA-MB-468, MDA-MB-231, MDA-MB-453, MCF-7 and HCC 1937). SC-2001 downregulated the phosphorylation of STAT3 (Tyr 705) and subsequently inhibited its transcriptional activities in a dose-dependent manner. STAT3-regulated proteins, including Mcl-1, survivin and cyclin D1, were also repressed by SC-2001. Over-expression of STAT3 in MDA-MB-468 cells protected cells from SC-2001-induced apoptosis. Moreover, SC-2001 enhanced the expression of SHP-1, a negative regulator of STAT3, in a time-dependent manner. The enhanced SHP-1 expression, in conjunction with increased SHP-1 phosphatase activity, was mediated by upregulated transcription. Furthermore, co-immunoprecipitation experiment showed that SC-2001 upregulated SHP-1 expression through enhanced transcription by RFX-1 transcription factor. Importantly, SC-2001 showed efficacious antitumor activity and p-STAT3 downregulation in MDA-MB-468 xenograft tumors. Conclusion: Our results suggest that SC-2001 induced apoptosis in breast cancer cells, and that this effect is mediated through RFX-1 upregulated SHP-1 expression and SHP-1-dependent STAT3 inactivation. (Supported by Yen Tjing Ling Medical Foundation; NSC 101-2325-B-075-006, NSC-102-2325-B-075-006 and NSC 100-2325-B-010-007; and V100-D-005-4) Citation Format: Chun-Yu Liu, Jung-Chen Su, Ling-Ming Tseng, Pei-Yi Chu, Wei-Tien Tai, Chung-Wai Shiau, Kuen-Feng Chen. Obatoclax analogue SC-2001 inhibits STAT3 phosphorylation by enhancing protein tyrosine phosphatase SHP-1 expression and induces apoptosis in human breast cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3803. doi:10.1158/1538-7445.AM2014-3803

  • Obatoclax analog SC-2001 inhibits STAT3 phosphorylation through enhancing SHP-1 expression and induces apoptosis in human breast cancer cells
    Breast Cancer Research and Treatment, 2014
    Co-Authors: Jung-chen Su, Chungwai Shiau, Mei-huei Ni, Ling-ming Tseng, Duen-shian Wang, Man-hsin Hung, Kuenfeng Chen
    Abstract:

    Interfering oncogenic STAT3 signaling is a promising anti-cancer strategy. We examined the efficacy and Drug Mechanism of an obatoclax analog SC-2001, a novel STAT3 inhibitor, in human breast cancer cells. Human breast cancer cell lines were used for in vitro studies. Apoptosis was examined by both flow cytometry and western blot. Signaling pathways were assessed by western blot. In vivo efficacy of SC-2001 was tested in xenograft nude mice. SC-2001 inhibited cell growth and induced apoptosis in association with downregulation of p-STAT3 (Tyr 705) in breast cancer cells. STAT3-regulated proteins, including Mcl-1, survivin, and cyclin D1, were repressed by SC-2001. Over-expression of STAT3 in MDA-MB-468 cells protected cells from SC-2001-induced apoptosis. Moreover, SC-2001 enhanced the expression of protein tyrosine phosphatase SHP-1, a negative regulator of STAT3. Furthermore, the enhanced SHP-1 expression, in conjunction with increased SHP-1 phosphatase activity, was mediated by upregulated transcription by RFX-1. Chromatin immunoprecipitation assay revealed that SC-2001 increased the binding capacity of RFX-1 to the SHP-1 promoter. Knockdown of either RFX-1 or SHP-1 reduced SC-2001-induced apoptosis, whereas ectopic expression of RFX-1 increased SHP-1 expression and enhanced the apoptotic effect of SC-2001. Importantly, SC-2001 suppressed tumor growth in association with enhanced RFX-1 and SHP-1 expression and p-STAT3 downregulation in MDA-MB-468 xenograft tumors. SC-2001 induced apoptosis in breast cancer cells, an effect that was mediated by RFX-1 upregulated SHP-1 expression and SHP-1-dependent STAT3 inactivation. Our study indicates targeting STAT3 signaling pathway may be a useful approach for the development of targeted agents for anti-breast cancer.

George C Prendergast - One of the best experts on this subject based on the ideXlab platform.

  • cell growth inhibition by farnesyltransferase inhibitors is mediated by gain of geranylgeranylated rhob
    Molecular and Cellular Biology, 1999
    Co-Authors: Peter F Lebowitz, George C Prendergast
    Abstract:

    Recent results have shown that the ability of farnesyltransferase inhibitors (FTIs) to inhibit malignant cell transformation and Ras prenylation can be separated. We proposed previously that farnesylated Rho proteins are important targets for alternation by FTIs, based on studies of RhoB (the FTI-Rho hypothesis). Cells treated with FTIs exhibit a loss of farnesylated RhoB but a gain of geranylgeranylated RhoB (RhoB-GG), which is associated with loss of growth-promoting activity. In this study, we tested whether the gain of RhoB-GG elicited by FTI treatment was sufficient to mediate FTI-induced cell growth inhibition. In support of this hypothesis, when expressed in Ras-transformed cells RhoB-GG induced phenotypic reversion, cell growth inhibition, and activation of the cell cycle kinase inhibitor p21WAF1. RhoB-GG did not affect the phenotype or growth of normal cells. These effects were similar to FTI treatment insofar as they were all induced in transformed cells but not in normal cells. RhoB-GG did not promote anoikis of Ras-transformed cells, implying that this response to FTIs involves loss-of-function effects. Our findings corroborate the FTI-Rho hypothesis and demonstrate that gain-of-function effects on Rho are part of the Drug Mechanism. Gain of RhoB-GG may explain how FTIs inhibit the growth of human tumor cells that lack Ras mutations.

  • cell growth inhibition by farnesyltransferase inhibitors is mediated by gain of geranylgeranylated rhob
    Molecular and Cellular Biology, 1999
    Co-Authors: Peter F Lebowitz, George C Prendergast
    Abstract:

    Recent results have shown that the ability of farnesyltransferase inhibitors (FTIs) to inhibit malignant cell transformation and Ras prenylation can be separated. We proposed previously that farnesylated Rho proteins are important targets for alternation by FTIs, based on studies of RhoB (the FTI-Rho hypothesis). Cells treated with FTIs exhibit a loss of farnesylated RhoB but a gain of geranylgeranylated RhoB (RhoB-GG), which is associated with loss of growth-promoting activity. In this study, we tested whether the gain of RhoB-GG elicited by FTI treatment was sufficient to mediate FTI-induced cell growth inhibition. In support of this hypothesis, when expressed in Ras-transformed cells RhoB-GG induced phenotypic reversion, cell growth inhibition, and activation of the cell cycle kinase inhibitor p21WAF1. RhoB-GG did not affect the phenotype or growth of normal cells. These effects were similar to FTI treatment insofar as they were all induced in transformed cells but not in normal cells. RhoB-GG did not promote anoikis of Ras-transformed cells, implying that this response to FTIs involves loss-of-function effects. Our findings corroborate the FTI-Rho hypothesis and demonstrate that gain-of-function effects on Rho are part of the Drug Mechanism. Gain of RhoB-GG may explain how FTIs inhibit the growth of human tumor cells that lack Ras mutations. Farnesyltransferase inhibitors (FTIs) are a novel class of antitumor agents whose development was based upon the discovery that posttranslational prenylation is required for the oncogenic properties of Ras (reviewed in references 17, 18, 40, and 56). Protein prenylation involves C-terminal addition of C15 (farnesyl) or C20 (geranylgeranyl) isoprenoids, each of them intermediates in cholesterol biosynthesis. Protein prenylation reactions are carried out by one of three enzymes in the cell: farnesyltransferase (FT), geranylgeranyltransferase type I (GGT-I), or geranylgeranyltransferase type II (GGT-II; Rab GGT). FT and GGT-I are related heterodimeric enzymes that share a common subunit. They mediate prenylation of members of the Ras and Rho subfamilies of the Ras superfamily of small GTPases that include C-terminal CAAX prenylation mo

Chunyu Liu - One of the best experts on this subject based on the ideXlab platform.

  • abstract 3803 obatoclax analogue sc 2001 inhibits stat3 phosphorylation by enhancing protein tyrosine phosphatase shp 1 expression and induces apoptosis in human breast cancer cells
    Cancer Research, 2014
    Co-Authors: Chunyu Liu, Chungwai Shiau, Ling-ming Tseng, Peiyi Chu, Weitien Tai, Kuenfeng Chen
    Abstract:

    Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Background: Interfering the oncogenic STAT3 signaling is considered as promising anti-cancer strategy. Previously, we have reported an obatoclax analogue, SC-2001, as a novel STAT3 inhibitor in hepatocellular carcinoma cells (Cancer Letter 2012). Here, we examined the efficacy and Drug Mechanism of SC-2001 in breast cancer cells. Methods: Human breast cancer cell lines were used for in vitro studies. Cell viability was examined by MTT assay. Apoptosis was examined by both flow cytometry and western blot. Signal transduction pathways in cells were assessed by western blot. Small interference RNA was used to knockdown SHP-1. Quantitative RT-PCR was used for assessing gene transcription. In vivo efficacy of SC-2001 was tested in xenografted nude mice. Results: SC-2001 inhibited cell growth and induced apoptosis in breast cancer cell lines (MDA-MB-468, MDA-MB-231, MDA-MB-453, MCF-7 and HCC 1937). SC-2001 downregulated the phosphorylation of STAT3 (Tyr 705) and subsequently inhibited its transcriptional activities in a dose-dependent manner. STAT3-regulated proteins, including Mcl-1, survivin and cyclin D1, were also repressed by SC-2001. Over-expression of STAT3 in MDA-MB-468 cells protected cells from SC-2001-induced apoptosis. Moreover, SC-2001 enhanced the expression of SHP-1, a negative regulator of STAT3, in a time-dependent manner. The enhanced SHP-1 expression, in conjunction with increased SHP-1 phosphatase activity, was mediated by upregulated transcription. Furthermore, co-immunoprecipitation experiment showed that SC-2001 upregulated SHP-1 expression through enhanced transcription by RFX-1 transcription factor. Importantly, SC-2001 showed efficacious antitumor activity and p-STAT3 downregulation in MDA-MB-468 xenograft tumors. Conclusion: Our results suggest that SC-2001 induced apoptosis in breast cancer cells, and that this effect is mediated through RFX-1 upregulated SHP-1 expression and SHP-1-dependent STAT3 inactivation. (Supported by Yen Tjing Ling Medical Foundation; NSC 101-2325-B-075-006, NSC-102-2325-B-075-006 and NSC 100-2325-B-010-007; and V100-D-005-4) Citation Format: Chun-Yu Liu, Jung-Chen Su, Ling-Ming Tseng, Pei-Yi Chu, Wei-Tien Tai, Chung-Wai Shiau, Kuen-Feng Chen. Obatoclax analogue SC-2001 inhibits STAT3 phosphorylation by enhancing protein tyrosine phosphatase SHP-1 expression and induces apoptosis in human breast cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3803. doi:10.1158/1538-7445.AM2014-3803

  • abstract 4515 a novel obatoclax derivative is a promising agent to overcome bortezomib s resistance in acute leukemia cells
    Cancer Research, 2011
    Co-Authors: Chunyu Liu, Chungwai Shiau, Hsinyu Kuo, Annlii Cheng, Chenghwai Tzeng, Kuenfeng Chen
    Abstract:

    Background: Our previous work showed that bortezomib, a reverse-inhibitor of the 26S proteasome, exerts differential cytotoxic effects to acute leukemia cells through down-regulation of phosphor-Akt (AACR 2010 abstract 1575). Interestingly, some acute leukemia cells (MOLT-3 and K562) are resistant to bortezomib. One of the resistant Mechanisms of bortezomib involves the abnormality in intrinsic apoptotic pathway members, the bcl-2 family. Of particular, it has been shown that bortezomib induces upregulation of Mcl-1 and that Mcl-1 accumulation may delay bortezomib-induced apoptosis. Obatoclax, a small molecule inhibitor of pro-survival BCL-2 members, including MCL-1, synergizes with bortezomib in mantle cell lymphoma (Blood 2007) and may overcome bortezomib resistance. Here, we designed a novel Mcl-1 inhibitor deriving from obatoclax, SC-2001, to overcome the resistance. Methods: MOLT-3 and K562 cell lines were used for in vitro studies. Apoptosis was examined by both flow cytometry and Western blot. Signal transduction pathways in cells were assessed by Western Blot. Gene silencing was done by small interference RNA (siRNA). Results: MOLT-3 and K562 were resistant to bortezomib up to 100nM. Upregulation of Mcl-1 expression after bortezomib treatment were evident in these cells. Interestingly, the addition of either obatoclax or SC-2001, restored the sensitivity of K562 and MOLT-3 cells to bortezomib. SC-2001, comparing to obatoclax, exerted better efficacy in sensitivity restoration of bortezomib in association with Mcl-1 downregulation in MOLT-3 cells. Moreover, down-regulation of Mcl-1 by siRNA overcame the apoptotic resistance to bortezomib in K562 cells. These data indicate that novel Mcl-1 inhibitors could restore bortezomib sensitivity in resistant acute leukemia cells. Conclusions: a novel Mcl-1 inhibitor SC-2001, is a promising agent to overcome bortezomib9s resistance in acute leukemia, further elucidating the Drug Mechanism regulating Mcl-1 inhibition is needed. Supported by VGHTPE 99DHA0100332 and 100DHA0100591 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 4515. doi:10.1158/1538-7445.AM2011-4515

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