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Mitochondrial fission causes cisplatin resistance under hypoxic conditions via ROS in ovarian cancer cells

Oncogene volume 38, pages 7089–7105 (2019)Cite this article

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Abstract

Mitochondria undergo fission and fusion continually for survival through the course of cellular adaption processes in response to changes in the surrounding environment. Dysregulated mitochondrial dynamics has been reported in various diseases including cancer. Under hypoxic conditions (<1% O2), the relationship between mitochondrial dynamics and sensitivity to cisplatin (CDDP) was examined in ovarian cancer cells. We found that hypoxia promoted mitochondrial fission and CDDP resistance in ovarian cancer cells. Hypoxia-induced reactive oxygen species (ROS) caused an increase in mitochondrial fission, a response abolished by free radical scavenging with N-acetylcysteine (NAC) and Trolox. Also, treatment of hydrogen peroxide (H2O2) decreased inhibitory p-Drp1 (Ser637) content and increased mitochondrial fission. Suppression of mitochondrial fission enhanced the CDDP sensitivity of hypoxic ovarian cancer cells. Lastly, in tumor spheroids from malignant ascites or tissues of patients with advanced-stage ovarian cancer, pretreatment with Mdivi-1 increased the CDDP sensitivity. Taken together, our results implicate that hypoxia-induced ROS trigger mitochondrial fission and CDDP resistance through downregulation of p-Drp1 (Ser637) and Mfn1 in ovarian cancer cells. Inhibition of Drp1 by Mdivi-1 treatment or si-Drp1 transfection increased CDDP sensitivity of ovarian cancer cells under hypoxia. Therefore, mitochondrial dynamics of cancer cells adapting to the hypoxic tumor microenvironment could be a potential target for anticancer therapy.

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Acknowledgements

This research was supported by the BK21 Plus Program of the Department of Agricultural Biotechnology, Seoul National University (Seoul, Korea), a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea [grant number HI16C2037], and Seoul National University Hospital (SNUH) research fund [grant number 04-2017-0530], as well as a grant from the Canadian Institutes of Health Research [grant number MOP-126144]. Also, we would like to thank Prof. Woo Ho Kim (Seoul National University, Republic of Korea) and his lab members for technical assistance in this study.

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Authors and Affiliations

  1. WCU Biomodulation, Department of Agricultural Biotechnology, Seoul National University, Seoul, 08826, Republic of Korea

    Youngjin Han & Yong Sang Song

  2. Cancer Research Institute, College of Medicine, Seoul National University, Seoul, 03080, Republic of Korea

    Youngjin Han, Boyun Kim, Untack Cho, In Sil Park & Yong Sang Song

  3. Department of Anesthesiology, McGovern Medical School, the University of Texas Health Science Center, Houston, TX, USA

    Boyun Kim

  4. Interdisciplinary Program in Cancer Biology, Seoul National University, Seoul, 03080, Republic of Korea

    Untack Cho & Yong Sang Song

  5. Department of Agricultural Biotechnology, Seoul National University, Seoul, 08826, Republic of Korea

    In Sil Park

  6. Department of Obstetrics and Gynecology, College of Medicine, Seoul National University, Seoul, 03080, Republic of Korea

    Se Ik Kim & Yong Sang Song

  7. Stephenson Cancer Center, the University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73012, USA

    Danny N. Dhanasekaran

  8. Departments of Obstetrics & Gynecology and Cellular & Molecular Medicine, University of Ottawa and Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada

    Benjamin K. Tsang

  9. State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macao, China

    Benjamin K. Tsang

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Han, Y., Kim, B., Cho, U. et al. Mitochondrial fission causes cisplatin resistance under hypoxic conditions via ROS in ovarian cancer cells. Oncogene 38, 7089–7105 (2019). https://doi.org/10.1038/s41388-019-0949-5

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