Targeting Signal Transducer and Activator of Transcription (STAT) for Anticancer Therapy

Abstract

Signal transducers and activators of transcription (STATs) are latent cytoplasmic transcription factors that are activated by phosphorylation. Activated STATs dimerize and translocate to the nucleus, where they bind to DNA and activate gene expression. STATs are vital molecules in the transduction of almost all cytokine signaling and have important roles in hematopoiesis, immunology, and tumor biology. There are seven STAT family members (STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6). The STAT pathways are activated by different mechanisms, including growth factor receptors with intrinsic tyrosine kinase activity, cytokine receptors whose activation is coupled with tyrosine kinases of the Jak family of kinases, non-receptor tyrosine kinases such as Src, G-protein-coupled receptors, and hormone receptors such as the prolactin receptor. Several proteins regulate the activity of STATs. These include phosphatases, suppressors of cytokine signaling molecules (SOCS), protein inhibitors of activated STATs (PIAS), and STAT-interacting LIM protein (SLIM). It is well known that STATs, especially STAT3 and STAT5, are constitutively activated in several cancer types. Constitutive activation of STAT3/STAT5 in cancer contributes to the generation of the malignant phenotype by increasing tumor cell proliferation, inducing resistance to apoptosis, enhancing angiogenesis, and downregulating innate immune mechanisms that hamper tumor expansion. As central molecules in several signaling pathways that contribute to oncogenesis, STATs are potential targets for therapeutic intervention. As yet, there are no approved agents for targeting activated STATs, but several such compounds are in development. Strategies for targeting STATs include inhibition of STAT dimerization, inhibition of DNA binding, use of oligodeoxynucleotides to target STAT mRNA or DNA binding, and inhibiting pathways that activate STATs. It is expected that after further study, several new agents will be available for targeting STATs in the therapy of patients with cancer.