Targeting mitochondrial ROS production to reverse the Epithelial-Mesenchymal Transition in breast cancer cells

Experimental evidence implicates reactive oxygen species (ROS) generation in the hypoxic
stabilization of hypoxia-inducible factor (HIF)-1α and in the subsequent expression of promoters
of tumor invasiveness and metastatic spread. However, the role played by mitochondrial ROS in
hypoxia-induced Epithelial-Mesenchymal Transition (EMT) activation is still unclear. This study
was aimed at testing the hypothesis that the inhibition of hypoxia-induced mitochondrial ROS
production, mainly at the mitochondrial Complex III UQCRB site, could result in the reversion of
EMT, in addition to decreased HIF-1α stabilization. The role of hypoxia-induced ROS increase in
HIF-1α stabilization and the ability of antioxidants, some of which directly targeting mitochondrial
Complex III, to block ROS production and HIF-1α stabilization and prevent changes in EMT markers
were assessed by evaluating ROS, HIF-1α and EMT markers on breast cancer cells, following 48 h
treatment with the antioxidants. The specific role of UQCRB in hypoxia-induced EMT was also
evaluated by silencing its expression through RNA interference and by assessing the effects of its
downregulation on ROS production, HIF-1α levels, and EMT markers. Our results confirm the
pivotal role of UQCRB in hypoxic signaling inducing EMT. Thus, UQCRB might be a new therapeutic
target for the development of drugs able to reverse EMT by blocking mitochondrial ROS production.