Control of TGF-?/Smad Signaling by mTOR in Prostate Cancer Transforming growth factor-beta (TGF-?) is well recognized to function as a potent tumor suppressor of the prostate, where it is believed to play a pivotal role in activation of cell death following androgen withdrawal. The function of TGF- ? is lost during carcinogenesis of the prostate;however, the underlying mechanisms for this loss of TGF- ? receptor function remain poorly studied. Studies conducted in Dr. David Danielpour's laboratory in the past several years have demonstrated that both the insulin-like growth factor-I (IGF-I) and the androgen receptor (AR) signaling pathways, which appear to be constitutively activated in a sizable proportion of prostate tumors, can block multiple steps in the TGF- ? signaling pathway and thus contribute to loss of the ability of TGF- ? to function as a tumor suppressor. The IGF-I/PI3K/Akt signaling pathway is commonly activated in prostate cancer through loss of PTEN function and/or elevation of IGF-I levels. We published the first reports that the IGF-I/PI3K/Akt pathway suppresses phospho-activation of Smads 2 and 3 through a mechanism that is dependent on the mammalian inhibitor of rapamycin (mTOR). However, the mechanism by which mTOR mediates such suppression is not known, and will be investigated as detailed in Aims 1 and 2 of this proposal.
These aims will test our hypothesis that an mTOR complex (TORC1) directly interacts with TGF- ? receptors and intercepts the TGF- ? signaling pathway.
Aim 2 will develop substantial mechanistic insight at the molecular level of how mTOR interacts with TGF- ? receptors and is able to modulate TGF- ? receptor signaling. Recent data from our laboratory suggests that inhibition of mTOR by rapamycin activates Smads 1, 3, 5 or 8 through their c- terminal phosphorylation in prostate cancer cell lines.
Aim 3 will validate the identity of the phospho-Smads that are phosphorylated by rapamycin, and test our hypothesis that Smads 1, 3, 5 or 8 are critical to mediation of the cytostatic effects of rapamycin on prostate cancer cells in culture and in growth of prostate tumor xenographs in athymic mice. Understanding the how PI3K/Akt/mTOR cross-talks with those TGF- ? and BMP signaling will likely have substantial therapeutic potential in prostate cancer.

Public Health Relevance

Transforming growth factor-beta (TGF- ?) is well recognized to function as a potent tumor suppressor of the prostate. This function of TGF- ? is lost in prostate through ways that remains unresolved. One way this could occur is through loss or functional inactivation of the tumor suppressor gene PTEN, reported in 30 to 50% of prostate cancers. Loss of PTEN activates tumor growth through the PI3K/Akt/mTOR signaling pathway. Our laboratory was first to report that Akt and mTOR signals intercept the ability of TGF- ? to suppress cell growth and induce apoptosis. We have studied components of how this may occur;however, much more effort is necessary before we can develop of clear picture of how these molecular interactions take place. In this research investigation we propose to undertake a major conceptual advance by seeking to address the more fundamental aspects of our model at a detailed molecular level, focusing on the interaction of mTOR on TGF- ? receptor signaling, and study the role Smads, direct mediators of TGF- ? and bone morphogenic proteins, in the biological activity and therapeutic action of inhibition of mTOR by rapamycin, using athymic mice as a host for growth of human prostate tumors. Understanding the molecular details behind such cross-talk is expected to substantially impact prostate cancer therapeutics.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cancer Molecular Pathobiology Study Section (CAMP)
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Salnikow, Konstantin
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Case Western Reserve University
Internal Medicine/Medicine
Schools of Medicine
United States
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Shankar, Eswar; Song, Kyung; Corum, Sarah L et al. (2016) A Signaling Network Controlling Androgenic Repression of c-Fos Protein in Prostate Adenocarcinoma Cells. J Biol Chem 291:5512-26
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Song, Kyung; Shankar, Eswar; Yang, Jiayi et al. (2013) Critical role of a survivin/TGF-?/mTORC1 axis in IGF-I-mediated growth of prostate epithelial cells. PLoS One 8:e61896
Wahdan-Alaswad, Reema S; Bane, Kara L; Song, Kyung et al. (2012) Inhibition of mTORC1 kinase activates Smads 1 and 5 but not Smad8 in human prostate cancer cells, mediating cytostatic response to rapamycin. Mol Cancer Res 10:821-33
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Song, Kyung; Wang, Hui; Krebs, Tracy L et al. (2010) DHT selectively reverses Smad3-mediated/TGF-beta-induced responses through transcriptional down-regulation of Smad3 in prostate epithelial cells. Mol Endocrinol 24:2019-29