At the Crossroads of TNF α Signaling and Cancer

Abstract: Tumor necrosis factor-alpha (TNFα) is a pleiotropic pro-inflammatory cytokine of the TNF superfamily. It regulates key cellular processes such as death, and proliferation besides its well-known role in immune response through activation of various intracellular signaling pathways (such as MAPK, Akt, NF-κB, etc.) via complex formation by ligand-activated TNFα receptors. TNFα tightly regulates the activity of key signaling proteins via their phosphorylation and/or ubiquitination which culminate in specific cellular responses. Deregulated TNFα signaling is implicated in inflammatory diseases, neurological disorders, and cancer. TNFα has been shown to exert opposite effects on cancer cells since it activates prosurvival as well as anti-survival pathways depending on various contexts such as cell type, concentration, cell density, etc. A detailed understanding of TNFα signaling phenomena is crucial for understanding its pleiotropic role in malignancies and its potential as a drug target or an anticancer therapeutic. This review enlightens complex cellular signaling pathways activated by TNFα and further discusses its role in various cancers.