mTOR inhibitors induce apoptosis in colon cancer cells via CHOP-dependent DR5 induction on 4E-BP1 dephosphorylation.

He K, Zheng X, Li M, Zhang L, Yu J
Oncogene. 2016 35 (2): 148-57

PMID: 25867072 · PMCID: PMC4603992 · DOI:10.1038/onc.2015.79

The mammalian target of rapamycin (mTOR) is commonly activated in colon cancer. mTOR complex 1 (mTORC1) is a major downstream target of the PI3K/ATK pathway and activates protein synthesis by phosphorylating key regulators of messenger RNA translation and ribosome synthesis. Rapamycin analogs Everolimus and Temsirolimus are non-ATP-competitive mTORC1 inhibitors, and suppress proliferation and tumor angiogenesis and invasion. We now show that apoptosis plays a key role in their anti-tumor activities in colon cancer cells and xenografts through the DR5, FADD and caspase-8 axis, and is strongly enhanced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and 5-fluorouracil. The induction of DR5 by rapalogs is mediated by the ER stress regulator and transcription factor CHOP, but not the tumor suppressor p53, on rapid and sustained inhibition of 4E-BP1 phosphorylation, and attenuated by eIF4E expression. ATP-competitive mTOR/PI3K inhibitors also promote DR5 induction and FADD-dependent apoptosis in colon cancer cells. These results establish activation of ER stress and the death receptor pathway as a novel anticancer mechanism of mTOR inhibitors.

MeSH Terms (19)

Adaptor Proteins, Signal Transducing Animals Antineoplastic Agents Apoptosis Cell Cycle Proteins Cell Line, Tumor Colonic Neoplasms Everolimus Female Humans Mice, Nude Phosphoproteins Phosphorylation Protein Kinase Inhibitors Receptors, TNF-Related Apoptosis-Inducing Ligand Sirolimus TOR Serine-Threonine Kinases Transcription Factor CHOP Xenograft Model Antitumor Assays

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