The AKT signaling pathway is important for the survival of multiple myeloma cells (MM). An important downstream target of AKT is the mammalian target of rapamycin (mTOR), which mediates phosphorylation of p70 and 4E-BP1, factors responsible for ribosome biogenesis and cap-dependent protein translation, respectively. Drugs that target mTOR, such as rapamycin, inhibit cap-dependent translation of critical proteins, resulting in cell cycle arrest and apoptosis. Numerous studies have demonstrated that the sensitivity to the anti-tumor effects of mTOR inhibitors correlates to heightened AKT activity, and we hypothesize that this is because cells with hyperactive AKT function depend upon mTOR-mediated cap-dependent translation of proteins required for survival. In these """"""""high"""""""" AKT cells, we expect that Mtor inhibitors block cap-dependent translation of these proteins, leading to cell cycle arrest and apoptosis. In contrast, MM cells with """"""""low"""""""" AKT function may utilize non-AKT/mTOR-dependent (i.e. cap-independent) translational pathways to express these critical proteins, making them resistant to mTOR inhibition. The cap-independent salvage pathway is mediated by internal ribosome entry sites (IRESes) located in the 5'UTR of specific mRNAs. In support of this hypothesis, we have recently demonstrated that translation of proteins with known IRES sequences (e.g. c-myc, VEGF) are differently expressed """"""""high"""""""" versus """"""""low"""""""" AKT MM cells. Therefore, this application will test whether AKT-mediated sensitivity of MM cells to mTOR inhibitors is due to inhibition of the cap-independent translation salvage pathways of critical survival and angiogenic proteins in vitro and in vivo. Will will also test whether the underlying mechanism(s) regulating cap-independent translation is mediated through IRES function of these gene transcripts. This K01 application will specifically provide mentored scientific, academic and career development training to the P.I. during a crucial period in his career and will facilitate his transition to an independent investigator in the field cancer biology.
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|Frost, P; Shi, Y; Hoang, B et al. (2007) AKT activity regulates the ability of mTOR inhibitors to prevent angiogenesis and VEGF expression in multiple myeloma cells. Oncogene 26:2255-62|