Restoration of mitochondria function as a target for cancer therapy

Abstract

Defective oxidative phosphorylation has a crucial role in the attenuation of mitochondrial function, which confers therapy resistance in cancer. Various factors, including endogenous heat shock proteins (HSPs) and exogenous agents such as dichloroacetate, restore respiratory and other physiological functions of mitochondria in cancer cells. Functional mitochondria might ultimately lead to the restoration of apoptosis in cancer cells that are refractory to current anticancer agents. Here, we summarize the key reasons contributing to mitochondria dysfunction in cancer cells and how restoration of mitochondrial function could be exploited for cancer therapeutics.

Figure 1

The Warburg effect in cancer cells. Aerobic glycolysis leads to pseudo hypoxic signals that upregulate hypoxia-inducible factor-1alpha (HIF-1α), which in turn regulates the expression of genes related to glucose metabolism. HIF-1α is induced by several factors, including hypoxia, growth factors, and oncogenes. HIF-1α induces the glucose transporter GLUT1, which results in an increase demand for glucose by cancer cells. It also enhances glycolysis via upregulation of glycolytic enzymes. HIF-1α-mediated upregulation of pyruvate dehydrogenase kinase (PDK) inhibits pyruvate conversion into acetyl-co-enzyme A (CoA) via suppression of pyruvate dehydrogenase (PDH). Lactate dehydrogenase A (LDHA) induction by HIF-1α leads to lactate production from pyruvate, which is transported to the external cell environment by monocarboxylate transporter-4 (MTC4), another target of HIF-1α. The anticancer agent dichloroacetate (DCA) suppresses PDK and restores PDH activity, leading to pyruvate entry into mitochondria to reactivate the tricarboxylic acid cycle (TCA) and oxidative phosphorylation (OXPHOS). Subsequently, activation of OXPHOS produced reactive oxygen species (ROS) and α-ketoglutarate, which ultimately lead to the induction of apoptosis, suppression of cancer cell growth and survival, inhibition of angiogenesis and metastasis, and overcoming of tumor resistance.