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

Oncogene volume 35, pages 148–157 (2016)Cite this article

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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.

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Acknowledgements

We thank Bert Vogelstein (Howard Hughes Medical Institute, Johns Hopkins University) for p53-KO HCT116, Richard J. Youle (NIH) for BAX/BAK-DKO HCT116 cells, Shi-Yong Sun (Emory University) for FADD-DN construct and Nahum Sonenberg (McGill University) for eIF4E construct. This work is supported by NIH grant CA129829, American Cancer Society grant RGS-10-124-01-CCE (YJ) and NIH grants CA106348, CA172136 (ZL). This project used the UPCI shared facilities including flow cytometry, animal and histopathology and were supported in part by award P30CA047904.

Author Contributions

JY and KH were involved in the conception and design of the study. KH, XZ and JY were involved in the development of methodology. KH, XZ, ML, LZ and JY were involved in the acquisition of data (provided animals, acquired and managed patients, provided facilities and so on). KH, XZ, ML and JY were involved in the analysis and interpretation of data (for example, statistical analysis, biostatistics and computational analysis). KH and JY were involved in the writing, review and/or revision of the manuscript. KH, XZ, LZ and JY were involved in the administrative, technical or material support (that is, reporting or organizing data and constructing databases). JY were involved in the study supervision.

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  1. K He and X Zheng: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    K He, X Zheng, M Li & J Yu

  2. University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    K He, X Zheng, M Li, L Zhang & J Yu

  3. Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    L Zhang

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Correspondence to J Yu.

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He, K., Zheng, X., Li, M. et al. mTOR inhibitors induce apoptosis in colon cancer cells via CHOP-dependent DR5 induction on 4E-BP1 dephosphorylation. Oncogene 35, 148–157 (2016). https://doi.org/10.1038/onc.2015.79

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