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mTOR and ERK MAPK signaling inhibits hormone-refractory prostate cancer in a preclinical mouse model
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H. Huang / Urologic Oncology: Seminars and Original Investigations 27 (2009) 221–232
Commentary on Targeting AKT/mTOR and ERK MAPK signaling inhibits hormone-refractory prostate cancer in a preclinical mouse model. Kinkade CW, Castillo-Martin M, Puzio-Kuter A, Yan J, Foster TH, Gao H, Sun Y, Ouyang X, Gerald WL, Cordon-Cardo C, Abate-Shen C, Department of Urology, Columbia University College of Physicians and Surgeons, New York, NY. J Clin Invest 2008;118:3051– 64 The AKT/mammalian target of rapamycin (AKT/mTOR) and ERK MAPK signaling pathways have been shown to cooperate in prostate cancer progression and the transition to androgen-independent disease. We have now tested the effects of combinatorial inhibition of these pathways on prostate tumorigenicity by performing preclinical studies using a genetically engineered mouse model of prostate cancer. We report here that combination therapy using rapamycin, an inhibitor of mTOR, and PD0325901, an inhibitor of MAPK kinase 1 (MEK; the kinase directly upstream of ERK), inhibited cell growth in cultured prostate cancer cell lines and tumor growth particularly for androgen-independent prostate tumors in the mouse model. We further showed that such inhibition leads to inhibition of proliferation and up-regulated expression of the apoptotic regulator Bcl-2-interacting mediator of cell death (Bim). Furthermore, analyses of human prostate cancer tissue microarrays demonstrated that AKT/mTOR and ERK MAPK signaling pathways are often coordinately deregulated during prostate cancer progression in humans. We therefore propose that combination therapy targeting AKT/mTOR and ERK MAPK signaling pathways may be an effective treatment for patients with advanced prostate cancer, in particular those with hormone-refractory disease.
Commentary Due to frequent mutation or deletion of the PTEN tumor suppressor the serine/threonine kinase Akt is often activated in human prostate cancers, which leads to the activation of its downstream target mammalian target of rapamycin (mTOR). In addition, the mitogen-activated protein kinase (MAPK) cascade (Ras/Raf/MEK/ERK) is also implicated in the tumorigenesis of human prostate cancers. Increasing evidence from tissue specimens obtained from patients who have received mTOR inhibitors suggests that ERK may be activated in response to mTOR interruption, highlighting the importance of inhibition of both Akt/mTOR and ERK MAPK pathways for the treatment of prostate cancers. Using a preclinical mouse model, Kinkade and colleagues demonstrate that simultaneous inhibition of mTOR and MEK/ERK resulted in substantially enhanced antitumor effects both in vitro and in vivo. Thus, findings from this study suggest that concurrent targeting of both Akt/mTOR and ERK MAPK signaling pathways could be one of the options for effective therapy of advanced prostate cancers in the clinic. doi:10.1016/j.urolonc.2008.12.004 Haojie Huang, Ph.D.
Commentary on Genomic loss of microRNA-101 leads to overexpression of histone methyltransferase EZH2 in cancer. Varambally S, Cao Q, Mani RS, Shankar S, Wang X, Ateeq B, Laxman B, Cao X, Jing X, Ramnarayanan K, Brenner JC, Yu J, Kim JH, Han B, Tan P, Kumar-Sinha C, Lonigro RJ, Palanisamy N, Maher CA, Chinnaiyan AM, Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI 48109. Science 2008;322:1695–9 Enhancer of zeste homolog 2 (EZH2) is a mammalian histone methyltransferase that contributes to the epigenetic silencing of target genes and that regulates the survival and metastasis of cancer cells. EZH2 is overexpressed in aggressive solid tumors by mechanisms that remain unclear. Here, we show that the expression and function of EZH2 in cancer cell lines is inhibited by microRNA-101 (miR-101). Analysis of human prostate tumors revealed that miR-101 expression decreases during cancer progression, paralleling an increase in EZH2 expression. One or both of the two genomic loci encoding miR-101 were somatically lost in 37.5% of clinically localized prostate cancers (6/16) and 66.7% of metastatic disease (22/33). We propose that genomic loss of miR-101 in cancer leads to overexpression of EZH2 and concomitant dysregulation of epigenetic pathways, resulting in cancer progression.
Commentary EZH2 functions in a multi-protein complex called polycomb group protein 2 (PRC2) that mediates epigenetic silencing of target genes by promoting histone H3 lysine 27 (H3K27) trimethylation. EZH2 has been found ovexpressed in various human cancers including prostate cancer while the mechanism of EZH2 dysregulation in cancers is largely unknown. In this study, Varambally and colleagues demonstrate that expression of EZH2 is suppressed by microRNA-101 (miR-101) in human cancer cell lines. Further studies demonstrate that miR-101 is frequently lost at the genomic level in both primary and metastatic prostate tumors. Importantly, loss of miR-101 was found to be inversely correlated with high levels of EZH2 in human prostate cancers. Thus, findings from this study not only reveal a mechanism by which the EZH2 level is elevated in human prostate cancers, they also suggest that restoring the levels of miR-101 in tumors may have therapeutic benefit by reprogramming the epigenetic program of tumor cells. doi:10.1016/j.urolonc.2008.12.005 Haojie Huang, Ph.D.
H. Huang / Urologic Oncology: Seminars and Original Investigations 27 (2009) 221–232
Commentary on Targeting AKT/mTOR and ERK MAPK signaling inhibits hormone-refractory prostate cancer in a preclinical mouse model. Kinkade CW, Castillo-Martin M, Puzio-Kuter A, Yan J, Foster TH, Gao H, Sun Y, Ouyang X, Gerald WL, Cordon-Cardo C, Abate-Shen C, Department of Urology, Columbia University College of Physicians and Surgeons, New York, NY. J Clin Invest 2008;118:3051– 64 The AKT/mammalian target of rapamycin (AKT/mTOR) and ERK MAPK signaling pathways have been shown to cooperate in prostate cancer progression and the transition to androgen-independent disease. We have now tested the effects of combinatorial inhibition of these pathways on prostate tumorigenicity by performing preclinical studies using a genetically engineered mouse model of prostate cancer. We report here that combination therapy using rapamycin, an inhibitor of mTOR, and PD0325901, an inhibitor of MAPK kinase 1 (MEK; the kinase directly upstream of ERK), inhibited cell growth in cultured prostate cancer cell lines and tumor growth particularly for androgen-independent prostate tumors in the mouse model. We further showed that such inhibition leads to inhibition of proliferation and up-regulated expression of the apoptotic regulator Bcl-2-interacting mediator of cell death (Bim). Furthermore, analyses of human prostate cancer tissue microarrays demonstrated that AKT/mTOR and ERK MAPK signaling pathways are often coordinately deregulated during prostate cancer progression in humans. We therefore propose that combination therapy targeting AKT/mTOR and ERK MAPK signaling pathways may be an effective treatment for patients with advanced prostate cancer, in particular those with hormone-refractory disease.
Commentary Due to frequent mutation or deletion of the PTEN tumor suppressor the serine/threonine kinase Akt is often activated in human prostate cancers, which leads to the activation of its downstream target mammalian target of rapamycin (mTOR). In addition, the mitogen-activated protein kinase (MAPK) cascade (Ras/Raf/MEK/ERK) is also implicated in the tumorigenesis of human prostate cancers. Increasing evidence from tissue specimens obtained from patients who have received mTOR inhibitors suggests that ERK may be activated in response to mTOR interruption, highlighting the importance of inhibition of both Akt/mTOR and ERK MAPK pathways for the treatment of prostate cancers. Using a preclinical mouse model, Kinkade and colleagues demonstrate that simultaneous inhibition of mTOR and MEK/ERK resulted in substantially enhanced antitumor effects both in vitro and in vivo. Thus, findings from this study suggest that concurrent targeting of both Akt/mTOR and ERK MAPK signaling pathways could be one of the options for effective therapy of advanced prostate cancers in the clinic. doi:10.1016/j.urolonc.2008.12.004 Haojie Huang, Ph.D.
Commentary on Genomic loss of microRNA-101 leads to overexpression of histone methyltransferase EZH2 in cancer. Varambally S, Cao Q, Mani RS, Shankar S, Wang X, Ateeq B, Laxman B, Cao X, Jing X, Ramnarayanan K, Brenner JC, Yu J, Kim JH, Han B, Tan P, Kumar-Sinha C, Lonigro RJ, Palanisamy N, Maher CA, Chinnaiyan AM, Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI 48109. Science 2008;322:1695–9 Enhancer of zeste homolog 2 (EZH2) is a mammalian histone methyltransferase that contributes to the epigenetic silencing of target genes and that regulates the survival and metastasis of cancer cells. EZH2 is overexpressed in aggressive solid tumors by mechanisms that remain unclear. Here, we show that the expression and function of EZH2 in cancer cell lines is inhibited by microRNA-101 (miR-101). Analysis of human prostate tumors revealed that miR-101 expression decreases during cancer progression, paralleling an increase in EZH2 expression. One or both of the two genomic loci encoding miR-101 were somatically lost in 37.5% of clinically localized prostate cancers (6/16) and 66.7% of metastatic disease (22/33). We propose that genomic loss of miR-101 in cancer leads to overexpression of EZH2 and concomitant dysregulation of epigenetic pathways, resulting in cancer progression.
Commentary EZH2 functions in a multi-protein complex called polycomb group protein 2 (PRC2) that mediates epigenetic silencing of target genes by promoting histone H3 lysine 27 (H3K27) trimethylation. EZH2 has been found ovexpressed in various human cancers including prostate cancer while the mechanism of EZH2 dysregulation in cancers is largely unknown. In this study, Varambally and colleagues demonstrate that expression of EZH2 is suppressed by microRNA-101 (miR-101) in human cancer cell lines. Further studies demonstrate that miR-101 is frequently lost at the genomic level in both primary and metastatic prostate tumors. Importantly, loss of miR-101 was found to be inversely correlated with high levels of EZH2 in human prostate cancers. Thus, findings from this study not only reveal a mechanism by which the EZH2 level is elevated in human prostate cancers, they also suggest that restoring the levels of miR-101 in tumors may have therapeutic benefit by reprogramming the epigenetic program of tumor cells. doi:10.1016/j.urolonc.2008.12.005 Haojie Huang, Ph.D.