The Janus-Faced Role of Antioxidants in Cancer Cachexia: New Insights on the Established Concepts

Figure 2

Role of ROS as a second messenger in the activation of proteolysis pathways. Tumor cells produce great amounts of proinflammatory cytokines and TGF-β family ligands, such as TNF-α and Mstn, respectively. Once in bloodstream, these mediators can easily reach skeletal muscle and activate several catabolic pathways, by signaling through their specific receptors. TNF-α induces the activation of NOX found in muscle fibers. The elevated activity of NOX and XO (XO is usually located within blood capillaries irrigating muscle) during cachexia is responsible for the great production of anion superoxide () molecules, which are rapidly converted into hydrogen peroxide (H₂O₂). Accumulation of H₂O₂ within muscle fibers induces sarcoplasmic reticulum stress and the subsequent massive release of calcium (Ca²⁺) ions. The increase of intracellular Ca²⁺ concentrations activates calpains 1 and 2 (Cap-1 and Cap-2), which in turn promote sarcomere disintegration and myofibrillar proteins liberation. H₂O₂ can activate IkB kinase (IKK) or SMAD3, leading to the phosphorylation of IkB and the dissociation of the NF-kB/IkB complex. Subsequently, NF-κB is released and ready to translocate into the nucleus. Additionally, P-SMAD2/3 transducers remove the sustained inhibitory phosphorylation of P-FOXO1/3 exerted by Akt and, therefore, allow its nuclear accumulation. Upon their entry into the nucleus, P-NF-κB and FOXO1/3 promote the transcriptional activation of MURF-1 and MAFbx, respectively. Then, MURF-1 and MAFbx tagged myofibrillar proteins with polyubiquitin chains to undergo proteolytic processing by the proteasome core (adapted from [27]).