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 20, 2018
Citation Information: J Clin Invest. 2018;128(9):4098-4114. https://doi.org/10.1172/JCI96804.
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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 7

Loss of ATP5H underlies aberrant activation of the HIF-1α/AKT/ERK signaling pathway.

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Loss of ATP5H underlies aberrant activation of the HIF-1α/AKT/ERK signal...
(A) mRNA levels of Hif1a (TC-1 cells) or HIF1A (CaSki cells) in TC-1 or CaSki cells without (P0) or with (P3) immune editing was probed by qRT-PCR. (B) Hydroxylated HIF-1α protein and VHL expression were probed by Western blotting (numbers below the blots are densitometric values). (C) Expression of HIF-1α as well as phosphorylated and total AKT and ERK in TC-1 or CaSki P3 cells was determined by Western blotting in the absence or presence of antioxidants (i.e., NAC or ascorbate). Numbers below the blots are densitometric values. (D) VEGF levels in supernatant were determined by ELISA in TC-1 or CaSki P3 cells treated with or without antioxidants. (E and F) TC-1 or CaSki P0 cells were transfected with the indicated siRNAs. (E) Western blot analysis of HIF-1α as well as p-AKT and p-ERK levels in these cells. Numbers below the blots are densitometric values. (F) ELISA of VEGF secretion by these cells. (G–K) siAtp5h- or siATP5H-transfected TC-1 and CaSki cells were cotransfected with the indicated siRNAs. (G) HIF-1α as well as p-AKT and p-ERK levels in these cells were probed by Western blotting (numbers below the blots are densitometric values). (H) VEGF levels in the supernatant of these cells were determined by ELISA. (I) Cells were exposed to E7-specific CTLs, cisplatin, or γ-irradiation. The frequency of apoptotic cells was determined by flow cytometric analysis of caspase-3 activation. The degree of stem-like (J) and invasive (K) phenotypes in these cells was determined by sphere-forming or Matrigel migration assay, respectively. All experiments were performed in triplicate under normoxic conditions. *P < 0.05 and **P < 0.01, by 2-tailed Student’s t test (A, H, and F–K) or 1-way ANOVA (D). Data represent the mean ± SD.