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mTORC1 enhancement of STIM1-mediated store-operated Ca2+ entry constrains tuberous sclerosis complex-related tumor development

Oncogene volume 32, pages 4702–4711 (2013)Cite this article

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Abstract

The protein complex of tuberous sclerosis complex (TSC)1 and TSC2 tumor suppressors is a key negative regulator of mammalian target of rapamycin (mTOR). Hyperactive mTOR signaling due to the loss-of-function of mutations in either TSC1 or TSC2 gene causes TSC, an autosomal dominant disorder featured with benign tumors in multiple organs. As the ubiquitous second messenger calcium (Ca2+) regulates various cellular processes involved in tumorigenesis, we explored the potential role of mTOR in modulation of cellular Ca2+ homeostasis, and in turn the effect of Ca2+ signaling in TSC-related tumor development. We found that loss of Tsc2 potentiated store-operated Ca2+ entry (SOCE) in an mTOR complex 1 (mTORC1)-dependent way. The endoplasmic reticulum Ca2+ sensor, stromal interaction molecule 1 (STIM1), was upregulated in Tsc2-deficient cells, and was suppressed by mTORC1 inhibitor rapamycin. In addition, SOCE repressed AKT1 phosphorylation. Blocking SOCE either by depleting STIM1 or ectopically expressing dominant-negative Orai1 accelerated TSC-related tumor development, likely because of restored AKT1 activity and enhanced tumor angiogenesis. Our data, therefore, suggest that mTORC1 enhancement of store-operated Ca2+ signaling hinders TSC-related tumor growth through suppression of AKT1 signaling. The augmented SOCE by hyperactive mTORC1-STIM1 cascade may contribute to the benign nature of TSC-related tumors. Application of SOCE agonists could thus be a contraindication for TSC patients. In contrast, SOCE agonists should attenuate mTOR inhibitors-mediated AKT reactivation and consequently potentiate their efficacy in the treatment of the patients with TSC.

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Acknowledgements

The mouse kidney tumor tissues were kindly provided by David J Kwiatkowski, Brigham and Women’s Hospital. This work was supported by the National Basic Research Program of China 973 Program Grant (2009CB522107 and 2009CB522203), the National Natural Science Foundation of China Grants (30971503 and 81130085), and the Ministry of Education of China 111 Project (B08007).

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Authors and Affiliations

  1. Department of Physiology and Pathophysiology, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

    H Peng, R Chen, Y Wang, J Duan, C Li, B Li, Y Jing, X Chen & H Zhang

  2. Department of Physiology, Capital Medical University, Beijing, China

    J Liu & J Wang

  3. Department of Immunology, Tianjin Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China

    Q Sun

  4. Department of Urology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China

    Q Mao

  5. Department of Respiratory Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China

    K-F Xu

  6. Institute of Biosciences & Technology, Center for Translational Cancer Research, Texas A&M Health Science Center, Houston, TX, USA

    C L Walker

  7. Department of Cardiology, Institute of Cardiovascular Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    J Li

  8. Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China

    H Zhang

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Peng, H., Liu, J., Sun, Q. et al. mTORC1 enhancement of STIM1-mediated store-operated Ca2+ entry constrains tuberous sclerosis complex-related tumor development. Oncogene 32, 4702–4711 (2013). https://doi.org/10.1038/onc.2012.481

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