Mitochondrial Redox Signaling and Tumor Progression

Abstract

Cancer cell can reprogram their energy production by switching mitochondrial oxidative phosphorylation to glycolysis. However, mitochondria play multiple roles in cancer cells, including redox regulation, reactive oxygen species (ROS) generation, and apoptotic signaling. Moreover, these mitochondrial roles are integrated via multiple interconnected metabolic and redox sensitive pathways. Interestingly, mitochondrial redox proteins biphasically regulate tumor progression depending on cellular ROS levels. Low level of ROS functions as signaling messengers promoting cancer cell proliferation and cancer invasion. However, anti-cancer drug-initiated stress signaling could induce excessive ROS, which is detrimental to cancer cells. Mitochondrial redox proteins could scavenger basal ROS and function as "tumor suppressors" or prevent excessive ROS to act as "tumor promoter". Paradoxically, excessive ROS often also induce DNA mutations and/or promotes tumor metastasis at various stages of cancer progression. Targeting redox-sensitive pathways and transcriptional factors in the appropriate context offers great promise for cancer prevention and therapy. However, the therapeutics should be cancer-type and stage-dependent.

Keywords: anti-oxidant proteins; apoptosis; cancer progression; mitochondria; redox signaling.

Figure 1

The redox signaling pathways of several key mitochondrial antioxidant systems and their roles in cellular apoptosis and proliferation. (A) Basal mitochondrial ROS activate cell survival and proliferation signaling to promote cancer progression. Mitochondrial anti-oxidant proteins could scavenger basal ROS and function as “tumor suppressors”. Deacetylase Sirt3 deacetylates SOD2 and enhances its activity. Loss of Sirt3 promotes oncogenesis, in part, by diminishing SOD2 activity; (B) Tumor micro-environmental stresses such as cytokines and anti-cancer drugs stimulate excessive ROS to activate apoptotic signaling. Under these settings, the mitochondrial anti-oxidant proteins could limit excessive ROS-induced apoptosis to act as “tumor promoter”.