mTORC1-Driven Translation Elongation Promotes Intestinal Tumor Initiation

Inactivation of the tumor suppressor adenomatous polyposis coli (APC) and subsequent activation of WNT signaling are strongly linked to the development of colorectal cancer, suggesting that therapies specifically targeting APC-deficient cells may be a promising therapeutic approach. The mTOR complex 1 (mTORC1) regulates epithelial cell growth and tumorigenesis via modulation of protein synthesis, but its role in WNT-driven intestinal proliferation is unknown. Faller and colleagues found that Apc deletion in mice enhanced activation of the mTORC1 effectors ribosomal protein S6 (RPS6) and eukaryotic translation initiation factor 4E (eIF4E) binding protein 1 (4EBP1) in a MYC-dependent manner. Treatment with the mTOR inhibitor rapamycin, which does not effectively inhibit 4EBP1, or deletion of the mTORC1 component Raptor decreased intestinal regeneration and blocked the proliferation of Apc-deficient intestinal epithelial cells but had no effect on the normal intestine. In addition, rapamycin treatment prevented tumor initiation and suppressed the growth of established intestinal tumors, indicating that mTORC1 is required for WNT-driven intestinal tumorigenesis. However, in contrast to previous studies suggesting that inhibition of translation initiation via 4EBP1 is rate limiting for cancer growth, mTORC1 activation following Apc deletion resulted in an increased rate of translation elongation that was necessary for intestinal proliferation. Consistent with this idea, mTORC1 signaling via RPS6 kinase (S6K), but not 4EBP1–eIF4E, and downstream inhibition of eukaryotic elongation factor 2 (eEF2) kinase (eEF2K), which negatively regulates eEF2 and translation elongation, were necessary for mTORC1-driven intestinal proliferation in the absence of Apc. Deletion of eEF2K enhanced intestinal regeneration in rapamycin-treated mice, resulting in mTORC1 inhibitor–resistant intestinal growth. Together, these results demonstrate an important role for mTORC1-mediated translation elongation and eEF2K in WNT-driven intestinal tumor initiation and suggest that targeting mTOR may be a viable strategy for chemoprevention and treatment of early-stage colorectal carcinoma.

Faller WJ, Jackson TJ, Knight JR, Ridgway RA, Jamieson T, Karim SA, et al. mTORC1-mediated translational elongation limits intestinal tumour initiation and growth. Nature 2014 Nov 5 [Epub ahead of print].