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.

HSP90A inhibition promotes anti-tumor immunity by reversing multi-modal resistance and stem-like property of immune-refractory tumors

“…Previously, we established a highly immune-resistant cervical tumor cell line, CaSki P3, generated from its immune susceptible parental cell line, CaSki P0, through three rounds of selection by cognate CTLs 22 . Notably, the immune-edited tumor cells (termed P3) were refractory to apoptotic death by multi-modality including cisplatin, γ-radiation, as well as cognate CTLs, whereas the parental cells (termed P0) remained sensitive to these 8 . To investigate potential targetable pathways for restoring sensitivity to multimodalities in the immune-edited tumor cells, we performed 2D protein electrophoresis and mass spectrometry in lysates derived from P0 and P3 cells.…”

“…1c), indicating a crucial role of HSP90A in a tumor-intrinsic resistance to CTL. Besides immune resistance, we reported the P3 cells have multi-modal resistance to chemotherapy and radiotherapy, and cancer stem cell (CSC)-like property 8,23,24 . Notably, siHSP90AA1 transfection re-sensitized P3 cells to chemotherapy and radiotherapy ( Fig.…”

“…5b). Furthermore, we previously reported the both TC-1 P3 and MDA-MB231 P3 cells have multimodal resistance to immunotherapy and chemotherapy, and CSClike property 8,25 . Notably, siHsp90aa1 or siHSP90AA1 transfection re-sensitized P3 cells to immunotherapy and chemotherapy, and reduced a stem-like phenotype (Supplementary Fig.…”

“…Furthermore, previous studies provide evidence that preferential selection and subsequent expansion of a subset of stem-like tumor cells with an undifferentiated phenotype contribute to therapeutic resistance [5][6][7] . In this regard, we had found that immune selection by immunotherapy drives the malignant evolution of tumors toward multi-modal resistance and stem-like phenotypes 8 . However, the potential link between the host immune-intrinsic mechanisms (i.e., cancer immunoediting) and the development of the malignant phenotypes of immunerefractory tumor cells is not well understood.…”

Role of hypoxia inducible factor-1 in cancer stem cells (Review)

“…The knockout of CSC marker protein CD44 induces glycolysis to OXPHOS via a complex signaling pathway involving HIF-1α (115). The loss of ATP synthase, especially the D subunit ATP5H, leads to the accumulation of ROS in cells and the stabilization of normoxic HIF-1α and activation of the HIF-1α pathway, affecting mitochondrial metabolic reprogramming, the production of stem-like ability, and therapeutic resistance (122). The α-KG analogue dimethyl 2-ketoglutarate allows excess succinate/fumarate to be transferred from the mitochondria to the cytoplasm, where it can impair prolyl hydroxylase and thus stabilize and activate HIF-1α, eventually leading to increased glycolysis and the acquisition of the stem-like characteristics of breast cancer cells (118).…”