Mitochondrial reprogramming via ATP5H loss promotes multimodal cancer therapy resistance

Kwon Ho Song, Jae Hoon Kim, Young Ho Lee, Hyun Cheol Bae, Hyo Jung Lee, Seon Rang Woo, Se Jin Oh, Kyung Mi Lee, Cassian Yee, Bo Wook Kim, Hanbyoul Cho, Eun Joo Chung, Joon Yong Chung, Stephen M. Hewitt, Tae Wook Chung, Ki Tae Ha, Young Ki Bae, Chih Ping Mao, Andrew Yang, T. C. WuTae Woo Kim

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

The host immune system plays a pivotal role in the emergence of tumor cells that are refractory to multiple clinical interventions including immunotherapy, chemotherapy, and radiotherapy. Here, we examined the molecular mechanisms by which the immune system triggers cross-resistance to these interventions. By examining the biological changes in murine and tumor cells subjected to sequential rounds of in vitro or in vivo immune selection via cognate cytotoxic T lymphocytes, we found that multimodality resistance arises through a core metabolic reprogramming pathway instigated by epigenetic loss of the ATP synthase subunit ATP5H, which leads to ROS accumulation and HIF-1α stabilization under normoxia. Furthermore, this pathway confers to tumor cells a stem-like and invasive phenotype. In vivo delivery of antioxidants reverses these phenotypic changes and resensitizes tumor cells to therapy. ATP5H loss in the tumor is strongly linked to failure of therapy, disease progression, and poor survival in patients with cancer. Collectively, our results reveal a mechanism underlying immune-driven multimodality resistance to cancer therapy and demonstrate that rational targeting of mitochondrial metabolic reprogramming in tumor cells may overcome this resistance. We believe these results hold important implications for the clinical management of cancer.

Original languageEnglish
Pages (from-to)4098-4114
Number of pages17
JournalJournal of Clinical Investigation
Volume128
Issue number9
DOIs
Publication statusPublished - 2018 Aug 31

ASJC Scopus subject areas

  • Medicine(all)

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    Song, K. H., Kim, J. H., Lee, Y. H., Bae, H. C., Lee, H. J., Woo, S. R., Oh, S. J., Lee, K. M., Yee, C., Kim, B. W., Cho, H., Chung, E. J., Chung, J. Y., Hewitt, S. M., Chung, T. W., Ha, K. T., Bae, Y. K., Mao, C. P., Yang, A., ... Kim, T. W. (2018). Mitochondrial reprogramming via ATP5H loss promotes multimodal cancer therapy resistance. Journal of Clinical Investigation, 128(9), 4098-4114. https://doi.org/10.1172/JCI96804