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Mitochondrial reprogramming via ATP5H loss promotes multimodal cancer therapy resistance

Authors
 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. Wu  ;  Tae Woo Kim 
Citation
 JOURNAL OF CLINICAL INVESTIGATION, Vol.128(9) : 4098-4114, 2018 
Journal Title
 JOURNAL OF CLINICAL INVESTIGATION 
ISSN
 0021-9738 
Issue Date
2018
Keywords
Cancer ; Immunology ; Oncology
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.
Files in This Item:
T201803870.pdf Download
DOI
10.1172/JCI96804
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Obstetrics and Gynecology (산부인과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Jae Hoon(김재훈) ORCID logo https://orcid.org/0000-0001-6599-7065
Cho, Hanbyoul(조한별) ORCID logo https://orcid.org/0000-0002-6177-1648
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/165339
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