Silencing of NAC1 Expression Induces Cancer Cells Oxidative Stress in Hypoxia and Potentiates the Therapeutic Activity of Elesclomol

Abstract

In order to survive under conditions of low oxygen, cancer cells can undergo a metabolic switch to glycolysis and suppress mitochondrial function in order to reduce oxygen consumption and prevent excessive generation of harmful reactive oxygen species (ROS). Nucleus accumbens-associated protein-1 (NAC1), a nuclear factor of the BTB/POZ gene family, has emerging roles in cancer. Here, we identified that NAC1-PDK3 pathway is required for suppression of mitochondrial mass, oxygen consumption, and ROS production and protects cancer cells from apoptosis in hypoxia. We show that NAC1 mediates suppression of mitochondrial function in hypoxia through inducing expression of pyruvate dehydrogenase kinase 3 (PDK3) by HIF-1α at the transcriptional level, thereby inactivating pyruvate dehydrogenase (PDH) and attenuating mitochondrial respiration. Re-expression of PDK3 in NAC1 absent cells rescued cells from hypoxia-induced metabolic stress and restored glycolysis in a mouse xenograft model, and demonstrated that knockdown of NAC1 expression can reinforce the antitumor efficacy of elesclomol, a pro-oxidative agent. Our findings define a novel mechanism by which NAC1 promotes stress resistance during cancer progression, and chemo-resistance in cancer therapy.