Mitochondrial reprogramming via ATP5H loss promotes multimodal cancer therapy resistance
- Authors
- Song, Kwon-Ho; Kim, Jae-Hoon; Lee, Young-Ho; Bae, Hyun Cheol; Lee, Hyo-Jung; Woo, Seon Rang; Oh, Se Jin; Lee, Kyung-Mi; Yee, Cassian; Kim, Bo Wook; Cho, Hanbyoul; Chung, Eun Joo; Chung, Joon-Yong; Hewitt, Stephen M.; Chung, Tae-Wook; Ha, Ki-Tae; Bae, Young-Ki; Mao, Chih-Ping; Yang, Andrew; Wu, T. C.; Kim, Tae Woo
- Issue Date
- 31-8월-2018
- Publisher
- AMER SOC CLINICAL INVESTIGATION INC
- Citation
- JOURNAL OF CLINICAL INVESTIGATION, v.128, no.9, pp.4098 - 4114
- Indexed
- SCIE
SCOPUS
- Journal Title
- JOURNAL OF CLINICAL INVESTIGATION
- Volume
- 128
- Number
- 9
- Start Page
- 4098
- End Page
- 4114
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/73709
- DOI
- 10.1172/JCI96804
- ISSN
- 0021-9738
- 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-1 alpha 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.
- Files in This Item
- There are no files associated with this item.
- Appears in
Collections - Graduate School > Department of Biomedical Sciences > 1. Journal Articles
Items in ScholarWorks are protected by copyright, with all rights reserved, unless otherwise indicated.