The mammalian target of rapamycin (mTOR) controls cell proliferation, growth, differentiation, motility and survival. Transformed or tumor cells with dysregulated mTOR signaling have shown higher susceptibility to inhibitors of mTOR than normal cells, suggesting mTOR inhibitors as potential tumor-selective therapeutic agents. Clinical trials have demonstrated that rapamycin and its derivatives, CCI-779, RAD001 and AP23573 (designated rapamycins) are promising anticancer drugs. They specifically block the function of mTOR, inhibiting growth of types of solid tumors with only mild side effects in patients. However, the anticancer mechanism of rapamycins remains obscure. While intense studies have focused on the role of mTOR in controlling cell proliferation and growth, little is known about how mTOR regulates cell motility. Preliminary studies show that rapamycin inhibits insulin-like growth factor-l (IGF-I) or 10% fetal bovine serum-stimulated motility of a panel of tumor cell lines in culture, suggesting a pivotal role of mTOR not only in cell proliferation but also in cell motility. The long-term goal of the applicant is to understand the molecular mechanism of IGF-l-mTOR signaling in tumorigenesis and metastasis, providing data for development of tumor-selective therapy. Because dysregulation of IGF-l-mTOR signaling pathway occurs frequently in human tumors, the proposed studies will focus on elucidating how mTOR regulates IGF-l-induced cell motility. With a combination of biochemical, molecular, cellular and genetic approaches, the specific aims of this proposal are to determine: (1) whether rapamycin inhibition of cell motility is a consequence of inhibition of mTOR kinase activity, and results from inhibition of signaling to S6K1 and/or 4E-BP1 established pathways downstream of mTOR, or through a novel pathway signaling through protein phosphatase 2A (PP2A) or other S/T phosphatases (PP4, PP5 and PP6); (2) how inhibition of mTOR by rapamycin prevents IGF-I- stimulated phosphorylation of focal adhesion proteins, including focal adhesion kinase (FAK), p130Cas and paxillin. Data generated from this work will not only provide invaluable insights into the mTOR-mediated signaling pathways, but also make significant contributions to the molecular understanding of tumor cell motility, which is crucial for development of metastasis. The findings may lead to design of novel drugs for the treatment and prevention of metastases. ? ? ? ?
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