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NOVEL INSIGHTS INTO BONE MORPHOGENETIC PROTEIN (BMP) AND MAMMALIAN TARGET OF RAPAMYCIN (mTOR) SIGNALING AXIS IN PROSTATE CANCER

Wahdan-Alaswad, Reema S.
http://rave.ohiolink.edu/etdc/view?acc_num=case1308175828

Abstract Details

2011, Doctor of Philosophy, Case Western Reserve University, Pharmacology.
Bone Morphogenetic Proteins (BMPs) are pleiotropic cytokines that play integral roles in embryogenesis, osteogenesis, and organogenesis. BMPs belong to the transforming growth factor-β (TGF-β) superfamily and are reported to function as tumor suppressors in early preneoplastic lesions of the prostate and tumor promoters in late stage prostate adenocarcinoma. Moreover, BMPs have been recently shown to be pivotal in controlling prostate tumorigenesis, and loss of BMP receptor function has been correlated to a higher Gleason grade in prostate cancer patients. During advanced prostate cancer, reports have shown that the IGF-I/PI3K/Akt/mTOR pathway is hyperactive in 50% of patients examined. In this light, we provide evidence that support that the IGF-I signaling axis inhibits BMP4-induced apoptosis, Smad-mediated gene expression, and BMP specific downstream targets. Suppression of the BMP4 signaling by IGF-I was reversed by direct genetic manipulation using enforced expression of wt-PTEN or DN-PI3K, use of chemical inhibitors against PI3K/Akt/mTOR, or small hairpin RNA-mediated silencing of mTORC1/2 subunits Raptor or Rictor. Our results support that IGF-I blocks BMP-induced transcription of Id1, Id2, and Id3, which are all downstream targets of BMP, through a PI3K/Akt/mTOR-dependent mechanism. Using various rat and human prostate epithelial cell lines as well as human prostate pathological specimens, we provide the first evidence that mTOR mediates inhibition of BMP-induced Smad1/5/8 activation. Deregulation of mTOR-mediated inhibition of BMP signaling pathway may be crucial to halting progression of prostate cancer formation. Furthermore, we report that direct inhibition of mTOR by rapamycin or rapalogs enhances BMP-mediated Smad1 and Smad5 activation in human prostate cancer cell lines and tissue. Utilization of lentivirus-based silencing and retroviral-based overexpression enabled us to show that Smad1 and Smad5 mediate rapamycin-induced cell death and activation of Id1. On the other hand, we showed that Smad8 represses rapamycin’s action in human prostate cell lines. All in all, the studies described here provide novel implications in the BMP and mTOR signaling axis in prostate cancer and new potential targets for the therapeutic intervention of this malignancy.
David Danielpour, PhD (Advisor)
Noa Noy, PhD (Committee Chair)
Bing-Cheng Wang, PhD (Committee Member)
Yu-Chung Yang, PhD (Committee Member)
Johannes von Lintig, PhD (Committee Member)
222 p.
Biology; Biomedical Research; Cellular Biology; Medicine; Molecular Biology; Oncology
BMP; TGF-beta; mTOR; Prostate Cancer; IGF-I

Recommended Citations

Citations

  • Wahdan-Alaswad, R. S. (2011). NOVEL INSIGHTS INTO BONE MORPHOGENETIC PROTEIN (BMP) AND MAMMALIAN TARGET OF RAPAMYCIN (mTOR) SIGNALING AXIS IN PROSTATE CANCER [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1308175828

    APA Style (7th edition)

  • Wahdan-Alaswad, Reema. NOVEL INSIGHTS INTO BONE MORPHOGENETIC PROTEIN (BMP) AND MAMMALIAN TARGET OF RAPAMYCIN (mTOR) SIGNALING AXIS IN PROSTATE CANCER. 2011. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1308175828.

    MLA Style (8th edition)

  • Wahdan-Alaswad, Reema. "NOVEL INSIGHTS INTO BONE MORPHOGENETIC PROTEIN (BMP) AND MAMMALIAN TARGET OF RAPAMYCIN (mTOR) SIGNALING AXIS IN PROSTATE CANCER." Doctoral dissertation, Case Western Reserve University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=case1308175828

    Chicago Manual of Style (17th edition)

case1308175828
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© 2011, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.