The Interplay of Reactive Oxygen Species, Hypoxia, Inflammation, and Sirtuins in Cancer Initiation and Progression

Figure 2

ROS are produced mainly in the mitochondria. Superoxides are rapidly detoxified by mitochondrial MnSOD as hydrogen peroxide or can cross mitochondrial membranes through the VDAC. Hydroperoxides travel easily to cytosol through membrane aquaporin. In addition to ROS coming from mitochondria, cytosolic ROS can originate from many endogenous or exogenous sources, including nutrients, radiation, microbiome, growth factors, cytokines, and other metabolisms. Proinflammatory inducible enzymes such as NADPH-oxidases (NOX), inducible nitric oxide synthase (iNOS), inducible cyclooxygenase (COX2), 5-lipoxigenase, and inducible heme-oxigenase-1 (HO-1) may produce an additional burst of ROS. HIF1α, NFκB, and HDACs, especially Sirtuins, are activated by ROS in synergy with the specific signaling from receptors and metabolism. Target genes of activated TFs are aimed at adaptation to hypoxia, proinflammatory harmful agents’ inactivation, and damage repair. ROS are also released in the extracellular space by secretion of granules of activated leukocytes or crossing plasma membrane through anionic channels (superoxides) or aquaporins (hydroperoxides). Extracellular ROS are important for defense (as in case of ROS released by eosinophils against macroparasite) and produce collateral damage not only in adjacent healthy tissues but also in distant tissues and organs, signaling the local damage and activating improper mechanisms of adaptation, remodeling, and chronic damage.