The Effect of Oxidative Phosphorylation on Cancer Drug Resistance

SIMPLE SUMMARY: Drug therapy is an important treatment for cancer patients; however, drug resistance severely affects the survival time and quality of life of cancer patients. Oxidative phosphorylation (OXHPOS) is an important metabolic process in cells that drives cancer drug resistance and exerts a significant influence on responses to anticancer therapy. Targeting OXPHOS can specifically eliminate cancer stem cells and delay the acquisition of drug resistance. Hence, OXPHOS has become a novel pharmacological target in cancer treatment. OXPHOS inhibitors in combination with conventional therapies have significantly increased the efficacy of treatments and attenuated resistance to anticancer drugs. ABSTRACT: Recent studies have shown that oxidative phosphorylation (OXPHOS) is a target for the effective attenuation of cancer drug resistance. OXPHOS inhibitors can improve treatment responses to anticancer therapy in certain cancers, such as melanomas, lymphomas, colon cancers, leukemias and pancreatic ductal adenocarcinoma (PDAC). However, the effect of OXPHOS on cancer drug resistance is complex and associated with cell types in the tumor microenvironment (TME). Cancer cells universally promote OXPHOS activity through the activation of various signaling pathways, and this activity is required for resistance to cancer therapy. Resistant cancer cells are prevalent among cancer stem cells (CSCs), for which the main metabolic phenotype is increased OXPHOS. CSCs depend on OXPHOS to survive targeting by anticancer drugs and can be selectively eradicated by OXPHOS inhibitors. In contrast to that in cancer cells, mitochondrial OXPHOS is significantly downregulated in tumor-infiltrating T cells, impairing antitumor immunity. In this review, we summarize novel research showing the effect of OXPHOS on cancer drug resistance, thereby explaining how this metabolic process plays a dual role in cancer progression. We highlight the underlying mechanisms of metabolic reprogramming in cancer cells, as it is vital for discovering new drug targets.