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NAMPT suppresses glucose deprivation-induced oxidative stress by increasing NADPH levels in breast cancer

Oncogene volume 35, pages 3544–3554 (2016)Cite this article

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Abstract

Nicotinamide phosphoribosyltransferase (NAMPT) is a rate-limiting enzyme involved in NAD+ biosynthesis. Although NAMPT has emerged as a critical regulator of metabolic stress, the underlying mechanisms by which it regulates metabolic stress in cancer cells have not been completely elucidated. In this study, we determined that breast cancer cells expressing a high level of NAMPT were resistant to cell death induced by glucose depletion. Furthermore, NAMPT inhibition suppressed tumor growth in vivo in a xenograft model. Under glucose deprivation conditions, NAMPT inhibition was found to increase the mitochondrial reactive oxygen species (ROS) level, leading to cell death. This cell death was rescued by treatment with antioxidants or NAD+. Finally, we showed that NAMPT increased the pool of NAD+ that could be converted to NADPH through the pentose phosphate pathway and inhibited the depletion of reduced glutathione under glucose deprivation. Collectively, our results suggest a novel mechanism by which tumor cells protect themselves against glucose deprivation-induced oxidative stress by utilizing NAMPT to maintain NADPH levels.

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Acknowledgements

This research was supported by the National R&D Program for Cancer Control, Ministry for Health and Welfare, Korea (1320240), by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (NRF-2014R1A2A2A01002931), by the Next-Generation BioGreen 21 Program, Rural Development Administration, Republic of Korea (PJ01121601) and by BK21 Plus funded by the Ministry of Education, Korea (10Z20130012243). We thank Kwan-Suk Lee at the POSTECH animal facility for assistance with animal experiments. Slide scanning images were obtained using Virtual Microscope in UNIST-Olympus Biomed Imaging Center (UOBC). We are grateful to Jin-Hoe Hur and UNIST-Olympus Biomed Imaging Center (UOBC) for providing the data of slide scanning images.

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Author notes

  1. S M Hong and C W Park: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology (POSTECH), Pohang, Korea

    S M Hong, C W Park, S W Kim, Y J Nam, J H Yu, J H Shin, S-H Im, K-T Kim, Y C Sung & K Y Choi

  2. Biokogen Inc. POSTECH Biotech Center #226, Pohang, Korea

    C W Park

  3. Academy of Immunology and Microbiology (AIM), Institute for Basic Science (IBS), Pohang, Korea

    C H Yun & S-H Im

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  1. S M Hong
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Correspondence to K Y Choi.

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Hong, S., Park, C., Kim, S. et al. NAMPT suppresses glucose deprivation-induced oxidative stress by increasing NADPH levels in breast cancer. Oncogene 35, 3544–3554 (2016). https://doi.org/10.1038/onc.2015.415

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