Mechanistic target of rapamycin complex 1 (mTORC1) is an important regulator of cell cycle progression and proliferation, and is a target of the inhibitor rapamycin. The 40S ribosomal S6 Kinase 1 (S6K1) is one of the best characterized downstream targets of mTORC1. The mTORC1/S6K1 pathway is hyperactivated in many types of cancer, contributing to cancer pathogenesis and progression.
Autophagy is a cellular mechanism conserved in all eukaryotes, whose role is to maintain homeostasis of the cell under stress-induced conditions by recycling intracellular components. In cancer, autophagy may serve to protect cancer cells from cell death and may contribute to acquired drug resistance. The mTORC1/S6K1 signaling pathway is an important regulator of autophagy. One of the concerns that arise with the use of mTORC1 inhibitors, such as rapamycin analogs (or rapalogs), is that rapalogs promote autophagy and cause cell senescence, which protects cancer cells from undergoing apoptosis.
Recent evidence suggests that a possible mechanism by which mTORC1 regulates autophagy may involve the tumor suppressor programmed cell death protein 4 (PDCD4), which is a downstream target of S6K1. Inhibition of mTORC1/S6K1 signaling causes upregulation of PDCD4 expression, which correlates with increased autophagy induction. We observed that suppressing PDCD4 expression in combination with rapamycin reduces autophagy and causes cancer cells to undergo cell death via apoptosis. Our results indicate that such strategy prevents rapamycin-induced upregulation of autophagy, while maintaining inhibition of mTORC1/S6K1 signaling, and promotes progression to apoptosis.
Citation Format: Anya Alayev, Rose B. Snyder, Marina K. Holz. Targeting rapamycin-induced autophagy in cancer. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr B18.