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Low-dose arsenic induces chemotherapy protection via p53/NF-κB-mediated metabolic regulation

Oncogene volume 33, pages 1359–1366 (2014)Cite this article

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Abstract

Most chemotherapeutical drugs kill cancer cells chiefly by inducing DNA damage, which unfortunately also causes undesirable injuries to normal tissues, mainly due to p53 activation. We report a novel strategy of normal tissue protection that involves p53/NF-κB coordinated metabolic regulation. Pretreatment of untransformed cells with low doses of arsenic induced concerted p53 suppression and NF-κB activation, which elicited a marked induction of glycolysis. Significantly, this metabolic shift provided cells effective protection against cytotoxic chemotherapy, coupling the metabolic pathway to cellular resistance. Using both in vitro and in vivo models, we demonstrated an absolute requirement of functional p53 in arsenic-mediated protection. Consistently, a brief arsenic pretreatment selectively protected only normal tissues, but not tumors, from toxicity of chemotherapy. An indispensable role of glycolysis in protecting normal tissues was demonstrated by using an inhibitor of glycolysis, 2-deoxyglucose, which almost totally abolished low-dose arsenic-mediated protection. Together, our work demonstrates that low-dose arsenic renders normal cells and tissues resistant to chemotherapy-induced toxicity by inducting glycolysis.

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Acknowledgements

This work was supported by NCI/NIH grants 2 R01 CA085679 and R01 CA125144 (to ZMY). We are grateful to Dr Gigi Lozano (The University of Texas MD Anderson Cancer Center, Houston, TX, USA) for the p53-mutant mice. Mouse imaging was performed by Suresh Prajapati, gratefully acknowledged.

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Authors and Affiliations

  1. Department of Radiation Oncology, Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    S Ganapathy, S Xiao, S-J Seo, R Lall, M Yang, T Xu, H Su, M Shadfan, C S Ha & Z-M Yuan

  2. Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA, USA

    S Ganapathy, M Yang & Z-M Yuan

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  1. S Ganapathy
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  2. S Xiao
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Correspondence to Z-M Yuan.

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Ganapathy, S., Xiao, S., Seo, SJ. et al. Low-dose arsenic induces chemotherapy protection via p53/NF-κB-mediated metabolic regulation. Oncogene 33, 1359–1366 (2014). https://doi.org/10.1038/onc.2013.81

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