title: mTOR inhibitors induce apoptosis in colon cancer cells via CHOP-dependent DR5 induction on 4E-BP1 dephosphorylation.
abstract: 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.
authors: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
authors: K
authors: K
authors: He
authors: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
authors: X
authors: X
authors: Zheng
authors: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
authors: M
authors: M
authors: Li
authors: University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.|Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors: L
authors: L
authors: Zhang
authors: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
authors: J
authors: J
authors: Yu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000068338:Everolimus / Q000494:pharmacology; D005260:Female; D006801:Humans; D008819:Mice, Nude; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051742:Transcription Factor CHOP / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; C497249:DDIT3 protein, human; C087000:EIF4EBP1 protein, human; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D051742:Transcription Factor CHOP; C401859:temsirolimus; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus