Mitochondrial reprogramming via ATP5H loss promotes multimodal cancer therapy resistance
Kwon-Ho Song, … , T.C. Wu, Tae Woo Kim
Kwon-Ho Song, … , T.C. Wu, Tae Woo Kim
Published August 31, 2018; First published August 20, 2018
Citation Information: J Clin Invest. 2018;128(9):4098-4114. https://doi.org/10.1172/JCI96804.
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Categories: Research Article Immunology Oncology

Mitochondrial reprogramming via ATP5H loss promotes multimodal cancer therapy resistance

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.

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

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Figure 1

Immune editing triggers epigenetic loss of ATP synthase in tumor cells.

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Immune editing triggers epigenetic loss of ATP synthase in tumor cells. ...
(A) ATP5H protein levels in TC-1 or CaSki tumor cells at various stages of immune editing were determined by Western blot analysis (numbers below each blot are densitometric values). (B) mRNA levels of Atp5h (TC-1 cells) or ATP5H (CaSki cells) in TC-1 or CaSki tumor cells at various stages of immune editing were determined by qRT-PCR. (A and B) N1, N2, and N3 were generated through serial selection by irrelevant antigen specific CTLs and were used as negative controls. (C) TC-1 or CaSki P0 and P3 tumor cells were treated with DMSO, 5-AzaC (5 μM), or TSA (100 nM). Atp5h (TC-1 cells) or ATP5H (CaSki cells) mRNA levels in these cells were probed by qRT-PCR. (D) The histone acetylation status of TC-1 or CaSki P0 and P3 cells was determined by ChIP using anti–histone H3 and H4 antibodies, followed by qPCR for the Atp5h or ATP5H promoter locus. (E) TC-1 or CaSki P3 cells were treated with or without TSA, and histone H4 acetylation at the Atp5h or ATP5H promoter was determined by ChIP-qPCR. (F–H) TC-1 or CaSki P3 cells were transfected with the indicated siRNAs. (F) Atp5h or ATP5H mRNA levels were determined by qPCR. (G) Protein levels of HDAC1 and ATP5H were determined by Western blot analysis (numbers below each blot are densitometric values). (H) Relative levels of AcH4 at the Atp5h or ATP5H promoter were assessed by qChIP. All experiments were performed in triplicate. *P < 0.05 and **P < 0.01, by 1-way ANOVA (B and C) or 2-tailed Student’s t test (D–F and H). Data represent the mean ± SD.