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Tumor-associated mutant p53 promotes cancer cell survival upon glutamine deprivation through p21 induction

Oncogene volume 36, pages 1991–2001 (2017)Cite this article

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Abstract

Cancer cells depend on glutamine to sustain their increased proliferation and manage oxidative stress, yet glutamine is often depleted at tumor sites owing to excessive cellular consumption and poor vascularization. We have previously reported that p53 protein, although a well-known tumor suppressor, can contribute to cancer cell survival and adaptation to low-glutamine conditions. However, the TP53 gene is frequently mutated in tumors, and the role of mutant p53 (mutp53) in response to metabolic stress remains unclear. Here, we demonstrate that tumor-associated mutp53 promotes cancer cell survival upon glutamine deprivation both in vitro and in vivo. Interestingly, cancer cells expressing mutp53 proteins are more resistant to glutamine deprivation than cells with wild-type p53. Depletion of endogenous mutp53 protein in human lymphoma cells leads to cell sensitivity to glutamine withdrawal, whereas expression of mutp53 in p53 null cells results in resistance to glutamine deprivation. Furthermore, we found that mutp53 proteins hyper-transactivate p53-target gene CDKN1A upon glutamine deprivation, thus triggering cell cycle arrest and promoting cell survival. Together, our results reveal an unidentified mechanism by which mutp53 confers oncogenic functions by promoting cancer cell adaptation to metabolic stress.

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Acknowledgements

We thank members of the Kong laboratory for helpful comments on the manuscript. We also thank Dr Zhaohui Feng (Rutgers University, New Jersey) for the mutp53 constructs. This work was supported by National Institutes of Health (NIH)/R01CA183989 to MK and the V Foundation for Cancer Research to MK. MK is the Pew Scholar in Biomedical Sciences and American Cancer Society Research Scholar (RSG-16-085-01-TBE). Research reported here includes work carried out in Core Facilities, supported by the NIH/NCI under grant number P30CA33572.

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Authors and Affiliations

  1. Department of Cancer Biology, Beckman Research Institute of City of Hope Cancer Center, Duarte, CA, USA

    T Q Tran, X H Lowman, M A Reid, C Mendez-Dorantes, M Pan, Y Yang & M Kong

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  1. T Q Tran
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Correspondence to M Kong.

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Tran, T., Lowman, X., Reid, M. et al. Tumor-associated mutant p53 promotes cancer cell survival upon glutamine deprivation through p21 induction. Oncogene 36, 1991–2001 (2017). https://doi.org/10.1038/onc.2016.360

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