The Effect of Oxidative Phosphorylation on Cancer Drug Resistance

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.

Keywords: cancer immunity; glycolysis; metabolism; oxidative phosphorylation; resistance.

Figure 1

Mitochondrial OXPHOS system. Electrons are transferred via NADH to Complex I and then transported to CoQ. Flavin-containing enzyme complexes can directly deliver electrons to CoQ. CoQ transfers electrons to Complex IV through Complex III and Cyt c. In this step, oxygen is reduced to water. Complexes I, III, and IV pump H⁺ from the mitochondrial matrix into the intermembrane space, which generates a proton gradient. Eventually, Complex V leverages this proton gradient to produce ATP.

Figure 2

Resistant cancer cells display high OXPHOS activity. Activation of various oncogenic signaling pathways contributes to cancer drug resistance by upregulating OXPHOS activity in certain cancers, including breast cancer, ovarian cancer, and melanoma.

Figure 3

OXPHOS plays a dual role in cancer immunity. (A) Anti-PD-L1 agent promotes mitochondrial function in tumor-reactive cytotoxic T lymphocytes (CTLs). (B) The Foxp3-mediated metabolic phenotype of Tregs may result in resistance to anticancer immunotherapy. (C) OXPHOS is required for M2 macrophage differentiation. (D) Neutrophils may mediate immune suppression in the tumor microenvironment (TME).