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Danny R Welch - One of the best experts on this subject based on the ideXlab platform.

  • the kiss1 Metastasis Suppressor appears to reverse the warburg effect by shifting from glycolysis to mitochondrial beta oxidation
    Journal of Molecular Medicine, 2017
    Co-Authors: Sharon Manley, Wen Liu, Danny R Welch
    Abstract:

    The shift by cancer cells toward aerobic glycolysis (Warburg effect) confers selective advantages by utilizing nutrients (e.g., lipids, amino acids, and nucleotides) to build biomass. Lipogenesis is generally enhanced, and its inhibition diminishes proliferation and survival. Re-expression of the Metastasis Suppressor KISS1 in human melanoma cells results in greater mitochondrial biogenesis, inhibition of glycolysis, utilization of beta-oxidation to provide energy, elevated oxidation of exogenous fatty acids, and increased expression of early-phase lipogenesis genes at both mRNA and protein levels. Correspondingly, the energy sensor AMPKβ is phosphorylated, resulting in inhibitory phosphorylation of acetyl-CoA carboxylase (ACC), which is linked to enhanced beta-oxidation. Furthermore, PGC1α is required for KISS1-mediated phosphorylation of ACC and Metastasis suppression. Collectively, these data further support the linkages between macromolecular metabolism and Metastasis. • KISS1 alters fatty acid metabolism. • There may be connections between Metastasis and metabolism. • PGC1alpha appears to be downstream mediator of KISS1 Metastasis suppression.

  • breast cancer Metastasis Suppressor 1 coordinately regulates Metastasis associated microrna expression
    International Journal of Cancer, 2009
    Co-Authors: Mick D Edmonds, Douglas R Hurst, Kedar S Vaidya, Lewis J Stafford, Dongquan Chen, Danny R Welch
    Abstract:

    Breast cancer Metastasis Suppressor 1 (BRMS1) suppresses Metastasis of multiple tumor types without blocking tumorigenesis. BRMS1 forms complexes with SIN3, histone deacetylases and selected transcription factors that modify Metastasis-associated gene expression (e.g., EGFR, OPN, PI4P5K1A, PLAU). microRNA (miRNA) are a recently discovered class of regulatory, noncoding RNA, some of which are involved in neoplastic progression. Based on these data, we hypothesized that BRMS1 may also exert some of its antimetastatic effects by regulating miRNA expression. MicroRNA arrays were done comparing small RNAs that were purified from metastatic MDA-MB-231 and MDA-MB-435 and their nonmetastatic BRMS1-transfected counterparts. miRNA expression changed by BRMS1 were validated using SYBR Green RT-PCR. BRMS1 decreased Metastasis-promoting (miR-10b, -373 and -520c) miRNA, with corresponding reduction of their downstream targets (e.g., RhoC which is downstream of miR-10b). Concurrently, BRMS1 increased expression of Metastasis suppressing miRNA (miR-146a, -146b and -335). Collectively, these data show that BRMS1 coordinately regulates expression of multiple Metastasis-associated miRNA and suggests that recruitment of BRMS1-containing SIN3:HDAC complexes to, as yet undefined, miRNA promoters might be involved in the regulation of cancer Metastasis.

  • breast cancer Metastasis Suppressor 1 up regulates mir 146 which suppresses breast cancer Metastasis
    Cancer Research, 2009
    Co-Authors: Douglas R Hurst, Mick D Edmonds, Kedar S Vaidya, Gary K Scott, Christopher C Benz, Danny R Welch
    Abstract:

    Breast cancer Metastasis Suppressor 1 (BRMS1) is a predominantly nuclear protein that differentially regulates expression of multiple genes, leading to suppression of Metastasis without blocking orthotopic tumor growth in multiple human and murine cancer cells of diverse origins. We hypothesized that miR-146 may be involved in the ability of BRMS1 to supress Metastasis because miR-146 expression is altered by BRMS1 and because BRMS1 and miR-146 are both associated with decreased signaling through the nuclear factor-κB pathway. BRMS1 significantly up-regulates miR-146a by 6- to 60-fold in metastatic MDA-MB-231 and MDA-MB-435 cells, respectively, and miR-146b by 40-fold in MDA-MB-435 as measured by real-time quantitative reverse transcription-PCR. Transduction of miR-146a or miR-146b into MDA-MB-231 down-regulated expression of epidermal growth factor receptor, inhibited invasion and migration in vitro, and suppressed experimental lung Metastasis by 69% and 84%, respectively (mean ± SE: empty vector = 39 ± 6, miR-146a = 12 ± 1, miR-146b = 6 ± 1). These results further support the recent notion that modulating the levels of miR-146a or miR-146b could have a therapeutic potential to suppress breast cancer Metastasis.

  • breast cancer Metastasis Suppressor 1 brms1 inhibits osteopontin transcription by abrogating nf κb activation
    Molecular Cancer, 2007
    Co-Authors: Rajeev S Samant, Danny R Welch, Muzaffer Cicek, Graham Casey, David W Clark, Rebecca A Fillmore, Brandon J Metge, Kondethimmana H Chandramouli, Ann F Chambers, Lalita A Shevde
    Abstract:

    Osteopontin (OPN), a secreted phosphoglycoprotein, has been strongly associated with tumor progression and aggressive cancers. MDA-MB-435 cells secrete very high levels of OPN. However Metastasis-suppressed MDA-MB-435 cells, which were transfected with breast cancer Metastasis Suppressor 1 (BRMS1), expressed significantly less OPN. BRMS1 is a member of mSin3-HDAC transcription co-repressor complex and has been shown to suppress the Metastasis of breast cancer and melanoma cells in animal models. Hence we hypothesized that BRMS1 regulates OPN expression. The search for a BRMS1-regulated site on the OPN promoter, using luciferase reporter assays of the promoter deletions, identified a novel NF-κB site (OPN/NF-κB). Electrophoretic mobility shift assays and chromatin immunoprecipitations (ChIP) confirmed this site to be an NF-κB-binding site. We also show a role of HDAC3 in suppression of OPN via OPN/NF-κB. Our results show that BRMS1 regulates OPN transcription by abrogating NF-κB activation. Thus, we identify OPN, a tumor-Metastasis activator, as a crucial downstream target of BRMS1. Suppression of OPN may be one of the possible underlying mechanisms of BRMS1-dependent suppression of tumor Metastasis.

  • breast cancer Metastasis Suppressor 1 inhibits gene expression by targeting nuclear factor κb activity
    Cancer Research, 2005
    Co-Authors: Muzaffer Cicek, Danny R Welch, Ryuichi Fukuyama, Nywana Sizemore, Graham Casey
    Abstract:

    Breast cancer Metastasis Suppressor 1 ( BRMS1 ) functions as a Metastasis Suppressor gene in breast cancer and melanoma cell lines, but the mechanism of BRMS1 suppression remains unclear. We determined that BRMS1 expression was inversely correlated with that of urokinase-type plasminogen activator ( uPA ), a prometastatic gene that is regulated at least in part by nuclear factor-κB (NF-κB). To further investigate the role of NF-κB in BRMS1-regulated gene expression, we examined NF-κB binding activity and found an inverse correlation between BRMS1 expression and NF-κB binding activity in MDA-MB-231 breast cancer and C8161.9 melanoma cells stably expressing BRMS1. In contrast, BRMS1 expression had no effect on activation of the activator protein-1 transcription factor. Further, we showed that suppression of both constitutive and tumor necrosis factor-α–induced NF-κB activation by BRMS1 may be due to inhibition of IκBα phosphorylation and degradation. To examine the relationship between BRMS1 and uPA expression in primary breast tumors, we screened a breast cancer dot blot array of normalized cDNA from 50 breast tumors and corresponding normal breast tissues. There was a significant reduction in BRMS1 mRNA expression in breast tumors compared with matched normal breast tissues (paired t test, P uPA gene expression ( P

Des R Richardson - One of the best experts on this subject based on the ideXlab platform.

  • Pharmacological targeting and the diverse functions of the Metastasis Suppressor, NDRG1, in cancer.
    Free radical biology & medicine, 2019
    Co-Authors: Kyung Chan Park, Zaklina Kovacevic, Jasmina Paluncic, Des R Richardson
    Abstract:

    Abstract N-myc downstream regulated gene-1 (NDRG1) is a potent Metastasis Suppressor that is regulated by hypoxia, metal ions including iron, the free radical nitric oxide (NO.), and various stress stimuli. This intriguing molecule exhibits diverse functions in cancer, inhibiting epithelial-mesenchymal transition (EMT), cell migration and angiogenesis by modulation of a plethora of oncogenes via cellular signaling. Thus, pharmacological targeting of NDRG1 signaling in cancer is a promising therapeutic strategy. Of note, novel anti-tumor agents of the di-2-pyridylketone thiosemicarbazone series, which exert the “double punch” mechanism by binding metal ions to form redox-active complexes, have been demonstrated to markedly up-regulate NDRG1 expression in cancer cells. This review describes the mechanisms underlying NDRG1 modulation by the thiosemicarbazones and the diverse effects NDRG1 exerts in cancer. As a major induction mechanism, iron depletion appears critical, with NO. also inducing NDRG1 through its ability to bind iron and generate dinitrosyl-dithiol iron complexes, which are then effluxed from cells. Apart from its potent anti-metastatic role, several studies have reported a pro-oncogenic role of NDRG1 in a number of cancer-types. Hence, it has been suggested that NDRG1 plays pleiotropic roles depending on the cancer-type. The molecular mechanism(s) underlying NDRG1 pleiotropy remain elusive, but are linked to differential regulation of WNT signaling and potentially differential interaction with the tumor Suppressor, PTEN. This review discusses NDRG1 induction mechanisms by metal ions and NO. and both the anti- and possible pro-oncogenic functions of NDRG1 in multiple cancer-types and compares the opposite effects this protein exerts on cancer progression.

  • interplay of the iron regulated Metastasis Suppressor ndrg1 with epidermal growth factor receptor egfr and oncogenic signaling
    Journal of Biological Chemistry, 2017
    Co-Authors: Sharleen V Menezes, Zaklina Kovacevic, Sumit Sahni, Des R Richardson
    Abstract:

    The iron-regulated Metastasis Suppressor N-myc downstream-regulated gene 1 (NDRG1) has been shown to inhibit numerous oncogenic signaling pathways in cancer cells. Recent findings have demonstrated that NDRG1 inhibits the ErbB family of receptors, which function as key inducers of carcinogenesis. NDRG1 attenuates ErbB signaling by inhibiting formation of epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor 2 (HER2) and HER2/HER3 heterodimers and by down-regulating EGFR via a mechanism involving its degradation. Understanding the complex interplay between NDRG1, iron, and ErbB signaling is vital for identifying novel, more effective targets for cancer therapy.

  • the Metastasis Suppressor n myc downstream regulated gene 1 ndrg1 down regulates the erbb family of receptors to inhibit downstream oncogenic signaling pathways
    Journal of Biological Chemistry, 2016
    Co-Authors: Zaklina Kovacevic, Darius J R Lane, Donghun Bae, Danuta S Kalinowski, Sumit Sahni, Sharleen V Menezes, Des R Richardson
    Abstract:

    N-MYC downstream-regulated gene-1 (NDRG1) is a potent growth and Metastasis Suppressor that acts through its inhibitory effects on a wide variety of cellular signaling pathways, including the TGF-β pathway, protein kinase B (AKT)/PI3K pathway, RAS, etc. To investigate the hypothesis that its multiple effects could be regulated by a common upstream effector, the role of NDRG1 on the epidermal growth factor receptor (EGFR) and other members of the ErbB family, namely human epidermal growth factor receptor 2 (HER2) and human epidermal growth factor receptor 3 (HER3), was examined. We demonstrate that NDRG1 markedly decreased the expression and activation of EGFR, HER2, and HER3 in response to the epidermal growth factor (EGF) ligand, while also inhibiting formation of the EGFR/HER2 and HER2/HER3 heterodimers. In addition, NDRG1 also decreased activation of the downstream MAPKK in response to EGF. Moreover, novel anti-tumor agents of the di-2-pyridylketone class of thiosemicarbazones, namely di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone and di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone, which markedly up-regulate NDRG1, were found to inhibit EGFR, HER2, and HER3 expression and phosphorylation in cancer cells. However, the mechanism involved appeared dependent on NDRG1 for di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone, but was independent of this Metastasis Suppressor for di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone. This observation demonstrates that small structural changes in thiosemicarbazones result in marked alterations in molecular targeting. Collectively, these results reveal a mechanism for the extensive downstream effects on cellular signaling attributed to NDRG1. Furthermore, this study identifies a novel approach for the treatment of tumors resistant to traditional EGFR inhibitors.

  • the Metastasis Suppressor ndrg1 modulates the phosphorylation and nuclear translocation of β catenin through mechanisms involving frat1 and pak4
    Journal of Cell Science, 2014
    Co-Authors: Runsen Jin, Zaklina Kovacevic, Minhua Zheng, Wensheng Liu, Fei Yue, Sharleen V Menezes, Des R Richardson
    Abstract:

    N-myc downstream-regulated gene 1 (NDRG1) is a potent Metastasis Suppressor that has been demonstrated to inhibit the transforming growth factor β (TGF-β)-induced epithelial-to-mesenchymal transition (EMT) by maintaining the cell-membrane localization of E-cadherin and β-catenin in prostate and colon cancer cells. However, the precise molecular mechanism remains unclear. In this investigation, we demonstrate that NDRG1 inhibits the phosphorylation of β-catenin at Ser33/37 and Thr41 and increases the levels of non-phosphorylated β-catenin at the plasma membrane in DU145 prostate cancer cells and HT29 colon cancer cells. The mechanism of inhibiting β-catenin phosphorylation involves the NDRG1-mediated upregulation of the GSK3β-binding protein FRAT1, which prevents the association of GSK3β with the Axin1-APC-CK1 destruction complex and the subsequent phosphorylation of β-catenin. Additionally, NDRG1 is shown to modulate the WNT-β-catenin pathway by inhibiting the nuclear translocation of β-catenin. This is mediated through an NDRG1-dependent reduction in the nuclear localization of p21-activated kinase 4 (PAK4), which is known to act as a transporter for β-catenin nuclear translocation. The current study is the first to elucidate a unique molecular mechanism involved in the NDRG1-dependent regulation of β-catenin phosphorylation and distribution.

  • the Metastasis Suppressor n myc downstream regulated gene 1 ndrg1 inhibits stress induced autophagy in cancer cells
    Journal of Biological Chemistry, 2014
    Co-Authors: Sumit Sahni, Zaklina Kovacevic, Darius J R Lane, Patric J. Jansson, Donghun Bae, Danuta S Kalinowski, Des R Richardson
    Abstract:

    N-myc downstream regulated gene 1 (NDRG1) is a potent Metastasis Suppressor with an undefined role in the stress response. Autophagy is a pro-survival pathway and can be regulated via the protein kinase-like endoplasmic reticulum kinase (PERK)/eIF2α-mediated endoplasmic reticulum (ER) stress pathway. Hence, we investigated the role of NDRG1 in stress-induced autophagy as a mechanism of inhibiting Metastasis via the induction of apoptosis. As thiosemicarbazone chelators induce stress and up-regulate NDRG1 to inhibit Metastasis, we studied their effects on the ER stress response and autophagy. This was important to assess, as little is understood regarding the role of the stress induced by iron depletion and its role in autophagy. We observed that the chelator, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), which forms redox-active iron and copper complexes, effectively induced ER stress as shown by activation of the PERK/eIF2α pathway. Dp44mT also increased the expression of the autophagic marker, LC3-II, and this was dependent on activation of the PERK/eIF2α axis, as silencing PERK prevented LC3-II accumulation. The effect of Dp44mT on LC3-II expression was at least partially due to iron-depletion, as this effect was also demonstrated with the classical iron chelator, desferrioxamine (DFO), and was not observed for the DFO-iron complex. NDRG1 overexpression also inhibited basal autophagic initiation and the ER stress-mediated autophagic pathway via suppression of the PERK/eIF2α axis. Moreover, NDRG1-mediated suppression of the pro-survival autophagic pathway probably plays a role in its anti-metastatic effects by inducing apoptosis. In fact, multiple pro-apoptotic markers were increased, whereas anti-apoptotic Bcl-2 was decreased upon NDRG1 overexpression. This study demonstrates the role of NDRG1 as an autophagic inhibitor that is important for understanding its mechanism of action.

Zaklina Kovacevic - One of the best experts on this subject based on the ideXlab platform.

  • Pharmacological targeting and the diverse functions of the Metastasis Suppressor, NDRG1, in cancer.
    Free radical biology & medicine, 2019
    Co-Authors: Kyung Chan Park, Zaklina Kovacevic, Jasmina Paluncic, Des R Richardson
    Abstract:

    Abstract N-myc downstream regulated gene-1 (NDRG1) is a potent Metastasis Suppressor that is regulated by hypoxia, metal ions including iron, the free radical nitric oxide (NO.), and various stress stimuli. This intriguing molecule exhibits diverse functions in cancer, inhibiting epithelial-mesenchymal transition (EMT), cell migration and angiogenesis by modulation of a plethora of oncogenes via cellular signaling. Thus, pharmacological targeting of NDRG1 signaling in cancer is a promising therapeutic strategy. Of note, novel anti-tumor agents of the di-2-pyridylketone thiosemicarbazone series, which exert the “double punch” mechanism by binding metal ions to form redox-active complexes, have been demonstrated to markedly up-regulate NDRG1 expression in cancer cells. This review describes the mechanisms underlying NDRG1 modulation by the thiosemicarbazones and the diverse effects NDRG1 exerts in cancer. As a major induction mechanism, iron depletion appears critical, with NO. also inducing NDRG1 through its ability to bind iron and generate dinitrosyl-dithiol iron complexes, which are then effluxed from cells. Apart from its potent anti-metastatic role, several studies have reported a pro-oncogenic role of NDRG1 in a number of cancer-types. Hence, it has been suggested that NDRG1 plays pleiotropic roles depending on the cancer-type. The molecular mechanism(s) underlying NDRG1 pleiotropy remain elusive, but are linked to differential regulation of WNT signaling and potentially differential interaction with the tumor Suppressor, PTEN. This review discusses NDRG1 induction mechanisms by metal ions and NO. and both the anti- and possible pro-oncogenic functions of NDRG1 in multiple cancer-types and compares the opposite effects this protein exerts on cancer progression.

  • interplay of the iron regulated Metastasis Suppressor ndrg1 with epidermal growth factor receptor egfr and oncogenic signaling
    Journal of Biological Chemistry, 2017
    Co-Authors: Sharleen V Menezes, Zaklina Kovacevic, Sumit Sahni, Des R Richardson
    Abstract:

    The iron-regulated Metastasis Suppressor N-myc downstream-regulated gene 1 (NDRG1) has been shown to inhibit numerous oncogenic signaling pathways in cancer cells. Recent findings have demonstrated that NDRG1 inhibits the ErbB family of receptors, which function as key inducers of carcinogenesis. NDRG1 attenuates ErbB signaling by inhibiting formation of epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor 2 (HER2) and HER2/HER3 heterodimers and by down-regulating EGFR via a mechanism involving its degradation. Understanding the complex interplay between NDRG1, iron, and ErbB signaling is vital for identifying novel, more effective targets for cancer therapy.

  • the Metastasis Suppressor n myc downstream regulated gene 1 ndrg1 down regulates the erbb family of receptors to inhibit downstream oncogenic signaling pathways
    Journal of Biological Chemistry, 2016
    Co-Authors: Zaklina Kovacevic, Darius J R Lane, Donghun Bae, Danuta S Kalinowski, Sumit Sahni, Sharleen V Menezes, Des R Richardson
    Abstract:

    N-MYC downstream-regulated gene-1 (NDRG1) is a potent growth and Metastasis Suppressor that acts through its inhibitory effects on a wide variety of cellular signaling pathways, including the TGF-β pathway, protein kinase B (AKT)/PI3K pathway, RAS, etc. To investigate the hypothesis that its multiple effects could be regulated by a common upstream effector, the role of NDRG1 on the epidermal growth factor receptor (EGFR) and other members of the ErbB family, namely human epidermal growth factor receptor 2 (HER2) and human epidermal growth factor receptor 3 (HER3), was examined. We demonstrate that NDRG1 markedly decreased the expression and activation of EGFR, HER2, and HER3 in response to the epidermal growth factor (EGF) ligand, while also inhibiting formation of the EGFR/HER2 and HER2/HER3 heterodimers. In addition, NDRG1 also decreased activation of the downstream MAPKK in response to EGF. Moreover, novel anti-tumor agents of the di-2-pyridylketone class of thiosemicarbazones, namely di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone and di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone, which markedly up-regulate NDRG1, were found to inhibit EGFR, HER2, and HER3 expression and phosphorylation in cancer cells. However, the mechanism involved appeared dependent on NDRG1 for di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone, but was independent of this Metastasis Suppressor for di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone. This observation demonstrates that small structural changes in thiosemicarbazones result in marked alterations in molecular targeting. Collectively, these results reveal a mechanism for the extensive downstream effects on cellular signaling attributed to NDRG1. Furthermore, this study identifies a novel approach for the treatment of tumors resistant to traditional EGFR inhibitors.

  • the Metastasis Suppressor ndrg1 modulates the phosphorylation and nuclear translocation of β catenin through mechanisms involving frat1 and pak4
    Journal of Cell Science, 2014
    Co-Authors: Runsen Jin, Zaklina Kovacevic, Minhua Zheng, Wensheng Liu, Fei Yue, Sharleen V Menezes, Des R Richardson
    Abstract:

    N-myc downstream-regulated gene 1 (NDRG1) is a potent Metastasis Suppressor that has been demonstrated to inhibit the transforming growth factor β (TGF-β)-induced epithelial-to-mesenchymal transition (EMT) by maintaining the cell-membrane localization of E-cadherin and β-catenin in prostate and colon cancer cells. However, the precise molecular mechanism remains unclear. In this investigation, we demonstrate that NDRG1 inhibits the phosphorylation of β-catenin at Ser33/37 and Thr41 and increases the levels of non-phosphorylated β-catenin at the plasma membrane in DU145 prostate cancer cells and HT29 colon cancer cells. The mechanism of inhibiting β-catenin phosphorylation involves the NDRG1-mediated upregulation of the GSK3β-binding protein FRAT1, which prevents the association of GSK3β with the Axin1-APC-CK1 destruction complex and the subsequent phosphorylation of β-catenin. Additionally, NDRG1 is shown to modulate the WNT-β-catenin pathway by inhibiting the nuclear translocation of β-catenin. This is mediated through an NDRG1-dependent reduction in the nuclear localization of p21-activated kinase 4 (PAK4), which is known to act as a transporter for β-catenin nuclear translocation. The current study is the first to elucidate a unique molecular mechanism involved in the NDRG1-dependent regulation of β-catenin phosphorylation and distribution.

  • the Metastasis Suppressor n myc downstream regulated gene 1 ndrg1 inhibits stress induced autophagy in cancer cells
    Journal of Biological Chemistry, 2014
    Co-Authors: Sumit Sahni, Zaklina Kovacevic, Darius J R Lane, Patric J. Jansson, Donghun Bae, Danuta S Kalinowski, Des R Richardson
    Abstract:

    N-myc downstream regulated gene 1 (NDRG1) is a potent Metastasis Suppressor with an undefined role in the stress response. Autophagy is a pro-survival pathway and can be regulated via the protein kinase-like endoplasmic reticulum kinase (PERK)/eIF2α-mediated endoplasmic reticulum (ER) stress pathway. Hence, we investigated the role of NDRG1 in stress-induced autophagy as a mechanism of inhibiting Metastasis via the induction of apoptosis. As thiosemicarbazone chelators induce stress and up-regulate NDRG1 to inhibit Metastasis, we studied their effects on the ER stress response and autophagy. This was important to assess, as little is understood regarding the role of the stress induced by iron depletion and its role in autophagy. We observed that the chelator, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), which forms redox-active iron and copper complexes, effectively induced ER stress as shown by activation of the PERK/eIF2α pathway. Dp44mT also increased the expression of the autophagic marker, LC3-II, and this was dependent on activation of the PERK/eIF2α axis, as silencing PERK prevented LC3-II accumulation. The effect of Dp44mT on LC3-II expression was at least partially due to iron-depletion, as this effect was also demonstrated with the classical iron chelator, desferrioxamine (DFO), and was not observed for the DFO-iron complex. NDRG1 overexpression also inhibited basal autophagic initiation and the ER stress-mediated autophagic pathway via suppression of the PERK/eIF2α axis. Moreover, NDRG1-mediated suppression of the pro-survival autophagic pathway probably plays a role in its anti-metastatic effects by inducing apoptosis. In fact, multiple pro-apoptotic markers were increased, whereas anti-apoptotic Bcl-2 was decreased upon NDRG1 overexpression. This study demonstrates the role of NDRG1 as an autophagic inhibitor that is important for understanding its mechanism of action.

Carrie W Rinkerschaeffer - One of the best experts on this subject based on the ideXlab platform.

  • Metastasis suppression the evolving role of Metastasis Suppressor genes for regulating cancer cell growth at the secondary site
    The Journal of Urology, 2003
    Co-Authors: Eric C Kauffman, Victoria L Robinson, Walter M Stadler, Mitchell H Sokoloff, Carrie W Rinkerschaeffer
    Abstract:

    ABSTRACTPurpose: The prevention and treatment of prostate cancer Metastasis continue to provide a significant clinical challenge. Identification of the rate limiting steps of Metastasis and their underlying molecular mechanisms may lead to new therapeutic targets and also allow more accurate risk stratification for clinical metastases. We review the literature supporting growth of disseminated tumor cells at the secondary site as a key rate limiting step in Metastasis. We also reviewed the definition, identification and characterization of Metastasis Suppressor genes, and discuss their evolving role in regulating this step.Materials and Methods: We performed MEDLINE searches and manual bibliographic reviews on the specific steps of Metastasis, including growth at the secondary site. In addition, we performed a comprehensive literature review to identify genes fitting the classic definition of a Metastasis Suppressor gene. The literature was also searched to assess the status of each gene in clinical cance...

  • Metastasis Suppressor genes a review and perspective on an emerging field
    Journal of the National Cancer Institute, 2000
    Co-Authors: Barbara A Yoshida, Danny R Welch, Mitchell M Sokoloff, Carrie W Rinkerschaeffer
    Abstract:

    Metastasis is the most lethal attribute of a cancer. There is a critical need for markers that will distinguish accurately those histologic lesions and disseminated cellswith a high probability of causing clinically important metastatic disease from those that will remain indolent. While the development of new diagnostic markers of Metastasis was the initial motivation for many studies, the biologic approach used to identify Metastasis-Suppressor genes has provided surprising insights into the in vivo mechanisms regulating the formation of metastases. This chapter reviews the evolving view of the mechanisms that regulate Metastasis and the importance of Metastasis-Suppressor genes in this process. The known Metastasis-Suppressor proteins or genes and the microcell-mediated chromosomal transfer strategy used to identify many of them are reviewed. New evidence for the role of these Metastasis-Suppressor activities (genes) in regulating the growth of disseminated cancer cells at the secondary site, the potential for the identification of novel therapeutic targets, and the multidisciplinary approach needed to translate this information into clinical tools for the treatment of metastatic disease are discussed.

  • mitogen activated protein kinase kinase 4 stress activated protein erk kinase 1 mkk4 sek1 a prostate cancer Metastasis Suppressor gene encoded by human chromosome 17
    Cancer Research, 1999
    Co-Authors: Barbara A Yoshida, Walter M Stadler, Zita Dubauskas, Marina Chekmareva, Thomas R Christiano, Carrie W Rinkerschaeffer
    Abstract:

    The introduction of a discontinuous ∼70-cM portion of human chromosome 17 significantly suppresses the metastatic ability of AT6.1 rat prostate cancer cells without affecting tumorigenicity (M. A. Chekmareva et al., Prostate, 33: 271–280, 1997). We have recently demonstrated that AT6.1 cells containing the ∼70-cM region (AT6.1-17-4 cells) escape from the primary tumor and arrest in the lung but are growth-inhibited unless the Metastasis Suppressor region is lost (M. A. Chekmareva et al., Cancer Res., 58: 4963–4969, 1998). A series of in vivo studies indicated that the observed growth inhibition was due to the effect of a gene(s) at the metastatic site (M. A. Chekmareva et al., Cancer Res., 58: 4963–4969, 1998). We have now identified the mitogen-activated protein kinase kinase 4/stress-activated protein/Erk kinase 1 (MKK4/SEK1) gene as a candidate Metastasis Suppressor gene encoded by the ∼70-cM region. AT6.1 cells were transfected with a MKK4/SEK1 expression construct, and the cells were tested in standard spontaneous Metastasis assays. Whereas the metastatic ability of the AT6.1-MKK4/SEK1 cells was significantly reduced as compared with that of transfection controls, the growth rate of the primary tumors was not affected; the average tumor volume at day 29 after injection was ∼2 cm. Furthermore, histological examination of the lungs of AT6.1-MKK4/SEK1 tumor-bearing animals revealed that the suppression by MKK4/SEK1 is due to an effect at the metastatic site, consistent with the phenotype conferred by the original ∼70-cM chromosomal region. These studies implicate MKK4/SEK1 as a Metastasis Suppressor gene encoded by human chromosome 17.

  • mitogen activated protein kinase kinase 4 stress activated protein erk kinase 1 mkk4 sek1 a prostate cancer Metastasis Suppressor gene encoded by human chromosome 17
    Cancer Research, 1999
    Co-Authors: Barbara A Yoshida, Walter M Stadler, Zita Dubauskas, Marina Chekmareva, Thomas R Christiano, Carrie W Rinkerschaeffer
    Abstract:

    The introduction of a discontinuous approximately 70-cM portion of human chromosome 17 significantly suppresses the metastatic ability of AT6.1 rat prostate cancer cells without affecting tumorigenicity (M. A. Chekmareva et al., Prostate, 33: 271-280, 1997). We have recently demonstrated that AT6.1 cells containing the approximately 70-cM region (AT6.1-17-4 cells) escape from the primary tumor and arrest in the lung but are growth-inhibited unless the Metastasis Suppressor region is lost (M. A. Chekmareva et al., Cancer Res., 58: 4963-4969, 1998). A series of in vivo studies indicated that the observed growth inhibition was due to the effect of a gene(s) at the metastatic site (M. A. Chekmareva et al., Cancer Res., 58: 4963-4969, 1998). We have now identified the mitogen-activated protein kinase kinase 4/stress-activated protein/Erk kinase 1 (MKK4/SEK1) gene as a candidate Metastasis Suppressor gene encoded by the approximately 70-cM region. AT6.1 cells were transfected with a MKK4/SEK1 expression construct, and the cells were tested in standard spontaneous Metastasis assays. Whereas the metastatic ability of the AT6.1-MKK4/SEK1 cells was significantly reduced as compared with that of transfection controls, the growth rate of the primary tumors was not affected; the average tumor volume at day 29 after injection was approximately 2 cm. Furthermore, histological examination of the lungs of AT6.1-MKK4/SEK1 tumor-bearing animals revealed that the suppression by MKK4/SEK1 is due to an effect at the metastatic site, consistent with the phenotype conferred by the original approximately 70-cM chromosomal region. These studies implicate MKK4/SEK1 as a Metastasis Suppressor gene encoded by human chromosome 17.

  • localization of Metastasis Suppressor gene s for rat prostatic cancer to the long arm of human chromosome 10
    Genes Chromosomes and Cancer, 1995
    Co-Authors: Naoki Nihei, Mitsuo Oshimura, Hiroaki Kuramochi, Carl J Barrett, Tomohiko Ichikawa, Youko Kawana, Ann M Killary, Hiroyuki Kugo, Carrie W Rinkerschaeffer, John T Isaacs
    Abstract:

    To examine the role of human chromosome 10 in development of prostatic cancer, we introduced human chromosome 10 into highly metastatic rat prostatic cancer cells by microcell-mediated chromosome transfer. Microcell hybrid cells introduced with human chromosome 10 showed suppression of the metastatic ability to the lung to some extent without any suppression of tumorigenicity, although the tumor growth rate decreased slightly. To minimize the region that contains Metastasis suppressive activity, the hybrid cells in Metastasis foci of lung were established in culture and reanalyzed for portions of human chromosome 10 retained in the Metastasis tissues. Cytogenetic and molecular analyses demonstrated that loss of the region between 10cen and D10S215 on human chromosome arm 10q was related to expression of the metastatic phenotype. These results demonstrate that the region between 10cen and D10S215 on human chromosome arm 10q contains at least one of the Metastasis Suppressor genes for rat prostatic cancer.

Barbara A Yoshida - One of the best experts on this subject based on the ideXlab platform.

  • Metastasis Suppressor genes a review and perspective on an emerging field
    Journal of the National Cancer Institute, 2000
    Co-Authors: Barbara A Yoshida, Danny R Welch, Mitchell M Sokoloff, Carrie W Rinkerschaeffer
    Abstract:

    Metastasis is the most lethal attribute of a cancer. There is a critical need for markers that will distinguish accurately those histologic lesions and disseminated cellswith a high probability of causing clinically important metastatic disease from those that will remain indolent. While the development of new diagnostic markers of Metastasis was the initial motivation for many studies, the biologic approach used to identify Metastasis-Suppressor genes has provided surprising insights into the in vivo mechanisms regulating the formation of metastases. This chapter reviews the evolving view of the mechanisms that regulate Metastasis and the importance of Metastasis-Suppressor genes in this process. The known Metastasis-Suppressor proteins or genes and the microcell-mediated chromosomal transfer strategy used to identify many of them are reviewed. New evidence for the role of these Metastasis-Suppressor activities (genes) in regulating the growth of disseminated cancer cells at the secondary site, the potential for the identification of novel therapeutic targets, and the multidisciplinary approach needed to translate this information into clinical tools for the treatment of metastatic disease are discussed.

  • mitogen activated protein kinase kinase 4 stress activated protein erk kinase 1 mkk4 sek1 a prostate cancer Metastasis Suppressor gene encoded by human chromosome 17
    Cancer Research, 1999
    Co-Authors: Barbara A Yoshida, Walter M Stadler, Zita Dubauskas, Marina Chekmareva, Thomas R Christiano, Carrie W Rinkerschaeffer
    Abstract:

    The introduction of a discontinuous ∼70-cM portion of human chromosome 17 significantly suppresses the metastatic ability of AT6.1 rat prostate cancer cells without affecting tumorigenicity (M. A. Chekmareva et al., Prostate, 33: 271–280, 1997). We have recently demonstrated that AT6.1 cells containing the ∼70-cM region (AT6.1-17-4 cells) escape from the primary tumor and arrest in the lung but are growth-inhibited unless the Metastasis Suppressor region is lost (M. A. Chekmareva et al., Cancer Res., 58: 4963–4969, 1998). A series of in vivo studies indicated that the observed growth inhibition was due to the effect of a gene(s) at the metastatic site (M. A. Chekmareva et al., Cancer Res., 58: 4963–4969, 1998). We have now identified the mitogen-activated protein kinase kinase 4/stress-activated protein/Erk kinase 1 (MKK4/SEK1) gene as a candidate Metastasis Suppressor gene encoded by the ∼70-cM region. AT6.1 cells were transfected with a MKK4/SEK1 expression construct, and the cells were tested in standard spontaneous Metastasis assays. Whereas the metastatic ability of the AT6.1-MKK4/SEK1 cells was significantly reduced as compared with that of transfection controls, the growth rate of the primary tumors was not affected; the average tumor volume at day 29 after injection was ∼2 cm. Furthermore, histological examination of the lungs of AT6.1-MKK4/SEK1 tumor-bearing animals revealed that the suppression by MKK4/SEK1 is due to an effect at the metastatic site, consistent with the phenotype conferred by the original ∼70-cM chromosomal region. These studies implicate MKK4/SEK1 as a Metastasis Suppressor gene encoded by human chromosome 17.

  • mitogen activated protein kinase kinase 4 stress activated protein erk kinase 1 mkk4 sek1 a prostate cancer Metastasis Suppressor gene encoded by human chromosome 17
    Cancer Research, 1999
    Co-Authors: Barbara A Yoshida, Walter M Stadler, Zita Dubauskas, Marina Chekmareva, Thomas R Christiano, Carrie W Rinkerschaeffer
    Abstract:

    The introduction of a discontinuous approximately 70-cM portion of human chromosome 17 significantly suppresses the metastatic ability of AT6.1 rat prostate cancer cells without affecting tumorigenicity (M. A. Chekmareva et al., Prostate, 33: 271-280, 1997). We have recently demonstrated that AT6.1 cells containing the approximately 70-cM region (AT6.1-17-4 cells) escape from the primary tumor and arrest in the lung but are growth-inhibited unless the Metastasis Suppressor region is lost (M. A. Chekmareva et al., Cancer Res., 58: 4963-4969, 1998). A series of in vivo studies indicated that the observed growth inhibition was due to the effect of a gene(s) at the metastatic site (M. A. Chekmareva et al., Cancer Res., 58: 4963-4969, 1998). We have now identified the mitogen-activated protein kinase kinase 4/stress-activated protein/Erk kinase 1 (MKK4/SEK1) gene as a candidate Metastasis Suppressor gene encoded by the approximately 70-cM region. AT6.1 cells were transfected with a MKK4/SEK1 expression construct, and the cells were tested in standard spontaneous Metastasis assays. Whereas the metastatic ability of the AT6.1-MKK4/SEK1 cells was significantly reduced as compared with that of transfection controls, the growth rate of the primary tumors was not affected; the average tumor volume at day 29 after injection was approximately 2 cm. Furthermore, histological examination of the lungs of AT6.1-MKK4/SEK1 tumor-bearing animals revealed that the suppression by MKK4/SEK1 is due to an effect at the metastatic site, consistent with the phenotype conferred by the original approximately 70-cM chromosomal region. These studies implicate MKK4/SEK1 as a Metastasis Suppressor gene encoded by human chromosome 17.