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p53/BNIP3-dependent mitophagy limits glycolytic shift in radioresistant cancer

Oncogene volume 38, pages 3729–3742 (2019)Cite this article

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Abstract

The role of p53 in genotoxic therapy-induced metabolic shift in cancers is not yet known. In this study, we investigated the role of p53 in the glycolytic shift in head and neck squamous cell carcinoma cell lines following irradiation. Isogenic p53-null radioresistant cancer cells established through cumulative irradiation showed decreased oxygen consumption and increased glycolysis with compromised mitochondria, corresponding with their enhanced sensitivity to drugs that target glycolysis. In contrast, radioresistant cancer cells with wild-type p53 preserved their primary metabolic profile with intact mitophagic processes and maintained their mitochondrial integrity. Moreover, we identified a previously unappreciated link between p53 and mitophagy, which limited the glycolytic shift through the BNIP3-dependent clearance of abnormal mitochondria. Thus, drugs targeting glycolysis could be used as an alternative strategy for overcoming radioresistant cancers, and the p53 status could be used as a biomarker for selecting participants for clinical trials.

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Acknowledgements

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future planning (2018R1A2A1A05020064, 2014R1A1A1003484, 2015R1A2A2A01003235), the Ministry of Education (2018R1D1A1B07042783), MRC grant funded by the Korean government (MSIT) (2018R1A5A2020732), the Global High-tech Biomedicine Technology Development Program of the NRF & Korea Health Industry Development Institute (KHIDI) (MSIP&MOHW) (2015M3D6A1065364), and the Asan Institute for Life Science (2017-073).

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  1. These authors contributed equally: Hyo Won Chang, Mi Ra Kim.

Authors and Affiliations

  1. Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea

    Hyo Won Chang, Hye Min Lee, Gui Chul Kim, Yoon Sun Lee, Myungjin Lee, Hye Jin Jang & Sang Yoon Kim

  2. Department of Otorhinolaryngology-Head and Neck Surgery, Inje University College of Medicine, Haeundae Paik Hospital, Busan, Republic of Korea

    Mi Ra Kim

  3. Department of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea

    Hyang Ju Lee, Hae Yun Nam & Seong Who Kim

  4. Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, Republic of Korea

    Kyung Eun Lee & Sang Yoon Kim

  5. Department of Otolaryngology, Ulsan University Hospital, Ulsan, Republic of Korea

    Jong Cheol Lee

  6. Research Institute of Pharmaceutical, College of Pharmacy, Seoul National University, Seoul, Republic of Korea

    Youngro Byun

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Chang, H.W., Kim, M.R., Lee, H.J. et al. p53/BNIP3-dependent mitophagy limits glycolytic shift in radioresistant cancer. Oncogene 38, 3729–3742 (2019). https://doi.org/10.1038/s41388-019-0697-6

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