Mtorc1 Enhances Bortezomib-Induced Death In Tsc-Null Cells By A C-Myc-Dependent Induction Of The Unfolded Protein Response

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL The ability of the proteasome inhibitor bortezomib to induce apoptosis of cancer cells is influenced by a variety of signaling pathways. We have found that control of c-MYC expression by the mammalian target of rapamycin complex-1 (mTORC1) plays a key role in determining drug sensitivity. Bortezomib treatment of Elt3 (rat TSC2-null leiomyoma) cells, that have high mTORC1 activity, activates the unfolded protein response (UPR) and apoptosis. Both effects were prevented by pretreatment of cells with the mTORC1 inhibitor, rapamycin, indicating mTORC1 dependence. Bortezomib also induced c-MYC expression in Elt3 cells in an mTORC1-dependent manner. c-MYC bound to the promoters of the UPR-induced transcription factors ATF4 and CHOP during bortezomib treatment. These data suggest direct involvement of an mTORC1/c-MYC-driven signaling pathway in the activation of the UPR. Consistent with this notion, overexpression of c-MYC in the presence of rapamycin was sufficient to rescue bortezomib induced CHOP and ATF4 expression, as well as apoptosis. These findings demonstrate that the induction ATF4/CHOP expression by mTORC1 via regulation of c-MYC is a major determinant in the ability of bortezomib to induce apoptosis of tumor cells. Since hypoxia and low nutrient levels in poorly vascularized tumors may contribute to down regulation of mTORC1, our data may help explain some of the difficulties in treating solid tumors with bortezomib and caution against the use of rapamycin in combination with proteasome inhibitors in cancer treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-247. doi:1538-7445.AM2012-LB-247