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Targeting mTOR suppressed colon cancer growth through 4EBP1/eIF4E/PUMA pathway

Cancer Gene Therapy volume 27, pages 448–460 (2020)Cite this article

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Abstract

Colorectal cancer is the third most frequently diagnosed malignancies among both men and women, which has an increased mortality but a poor prognosis. Targeting mTOR becomes an effective approach that shows promising antitumor activities in various cancers including colonic carcinoma. However, the potential mechanism against colon cancer remains incompletely understood. Here, we demonstrated that the anti-cancer effect of AZD8055 and OSI-027 is at least in part modulated by the gradual process of apoptosis initiation, progressing from mTOR suppression, 4EBP1 dephosphorylation, or EZH2 suppression, thereby leading to PUMA-dependent apoptosis via the intrinsic mitochondrial pathway. Furthermore, AZD8055 inhibited colorectal cancer tumor growth in mice significantly. PUMA deletion caused resistance of dual mTOR inhibitors, suggesting PUMA mediated carcinogenesis in vitro and in vivo. Collectively, these findings established a vital status of PUMA in driving the antineoplastic efficacy of targeting mTOR by AZD8055 and OSI-027 and offered the rationales for the current clinical assessment.

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Acknowledgements

We would like to thank the support of the National Natural Science Foundation of China (31801140 and 31701132), the Basic Research Program of Shenzhen Municipal Science and Technology Innovation Committee (JCYJ20160530192802733), the Fundamental Research Funds for the Central South Universities (Nos. 531118040098 and 14700–502044001), and the start funds from College of Biology, Hunan University.

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  1. These authors contributed equally: Huanan Wang, Yeying Liu, Jie Ding

Authors and Affiliations

  1. Department of Veterinary Medicine, College of Animal Sciences, Zhejiang University, Hangzhou, China

    Huanan Wang, Yue Ao, Yi Hong & Lefeng Wang

  2. College of Biology, Hunan University, Changsha, China

    Huanan Wang, Yeying Liu, Yuan Huang, Jing Liu, Nannan Liu & Yingjie Zhang

  3. Department of Health Management, The Third Xiangya Hospital, Central South University, Changsha, China

    Yeying Liu & Jiangang Wang

  4. Department of Emergency Surgery, The Second Military Medical University, Shanghai, China

    Jie Ding

  5. Department of Laboratory Medicine, Xiangya School of Medicine, Central South University, Changsha, China

    Lingling Zhang

  6. Shenzhen Institute, Hunan University, Shenzhen, China

    Yingjie Zhang

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Wang, H., Liu, Y., Ding, J. et al. Targeting mTOR suppressed colon cancer growth through 4EBP1/eIF4E/PUMA pathway. Cancer Gene Ther 27, 448–460 (2020). https://doi.org/10.1038/s41417-019-0117-7

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