Targeting mTORC1 Suppresses Proliferation of Keratinocyte Stem Cells and Inhibits Skin Tumor Promotion in Mice

The study demonstrated that targeting mTORC1 with rapamycin effectively blocked downstream signaling and inhibited epidermal hyperproliferation and skin tumor promotion in both wild-type and BK5.AktWT transgenic mice, with higher doses required for the latter. Elevated Akt expression in transgenic mice led to increased label retaining cells (LRCs) and K15 expressing cells in hair follicles, which were significantly inhibited by rapamycin. Additionally, BK5.PRAS40T246A transgenic mice, which overexpress a mutant form of PRAS40, showed a 63% reduction in skin tumor development, reduced mTORC1 signaling, increased autophagy, and elevated apoptosis following TPA treatment. These findings highlighted the significant role of mTORC1 signaling in skin tumor promotion and its potential as a target for cancer chemoprevention.