Structure, function, signaling pathways and clinical therapeutics: The translational potential of STAT3 as a target for cancer therapy

Cancer remains one of the most difficult human diseases to overcome because of its complexity and diversity. Signal transducers and transcriptional activators 3 (STAT3) protein has been found to be overexpressed in a wide range of cancer types. Hyperactivation of STAT3 is particularly associated with low survival in cancer patients. This review summarizes the specific molecular mechanisms of STAT3 in cancer development. STAT3 is activated by extracellular signals in the cytoplasm, interacts with different enzymes in the nucleus, mitochondria or endoplasmic reticulum, and subsequently participates in cancer development. The phosphorylated STAT3 at tyrosine 705 site (YP-STAT3) enters the nucleus and regulates a number of tumor-related biological processes such as angiogenesis, migration invasion, cell proliferation and cancer cell stemness. In contrast, the phosphorylated STAT3 at serine 727 site (SP-STAT3) is found on the mitochondria, affects electron respiration transport chain activity and thereby prevents tumor cell apoptosis. SP-STAT3 also appears on the mitochondria-associated endoplasmic reticulum membrane, influences the flow of Ca²⁺, and affects tumor progression. In addition, we summarize the direct and indirect inhibitors of STAT3 which are currently undergoing clinical studies. Some of them such as TTI101 and BBI608 have been approved by the FDA for the treatment of certain cancers. All in all, STAT3 plays an important role in cancer progression and becomes a potential target for cancer treatment.