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 8

Chemoselection triggers ATP5H lost, mitochondrial reprogramming, and resistance to multimodal therapy.

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Chemoselection triggers ATP5H lost, mitochondrial reprogramming, and res...
(A) ATP5H and HIF-1α levels were probed in drug-sensitive (P) or refractory (CR) human cancer cells by Western blotting (numbers below blots are densitometric values). Note: CP20 is a refractory version of A2780 cells. (B) ROS levels (O2–) were determined by MitoSOX staining, followed by flow cytometric analysis. (C) P or CR cells were exposed to granzyme B, cisplatin, or γ-irradiation. The frequency of caspase-3–positive apoptotic cells was determined by flow cytometric analysis. (D) The degree of stem-like and invasive phenotypes of cells was determined by sphere-forming or Matrigel migration assay. Scale bars: 100 μm (top) and 20 μm (bottom), respectively. (E–G) CR tumor cells were incubated with or without antioxidants (NAC). (E) HIF-1α levels were probed by Western blotting (numbers below blots are densitometric values). (F) Cells were exposed to granzyme B, cisplatin, or γ-irradiation. The frequency of caspase-3–positive apoptotic cells was determined by flow cytometric analysis. (G) The degree of stem-like and invasive phenotypes in cells was determined by sphere-forming or Matrigel migration assay. Scale bars: 100 μm (top) and 20 μm (bottom), respectively. (H) NOD/SCID mice were inoculated with CaSki-CR cells. Mice were administered NAC (0.1 mg/kg) via chitosan hydrogel, together with cisplatin (2 mg/kg), at the indicated time points. (I) Tumor size was measured every 3 days. (J) The average tumor weight in each group was measured 21 days after tumor challenge. (K) Kaplan-Meier analysis of survival in each group. All in vitro experiments were performed in triplicate under normoxic conditions. For in vivo experiments, 10 mice from each group were used. *P < 0.05, **P < 0.01, and ***P < 0.001, by 2-tailed Student’s t test (B–D, F, and G), ANOVA (I and J), or log-rank test (K). Data represent the mean ± SD.