The Multifaced Role of STAT3 in Cancer and Its Implication for Anticancer Therapy

Abstract

Signal transducer and activator of transcription (STAT) 3 is one of the most complex regulators of transcription. Constitutive activation of STAT3 has been reported in many types of tumors and depends on mechanisms such as hyperactivation of receptors for pro-oncogenic cytokines and growth factors, loss of negative regulation, and excessive cytokine stimulation. In contrast, somatic STAT3 mutations are less frequent in cancer. Several oncogenic targets of STAT3 have been recently identified such as c-myc, c-Jun, PLK-1, Pim1/2, Bcl-2, VEGF, bFGF, and Cten, and inhibitors of STAT3 have been developed for cancer prevention and treatment. However, despite the oncogenic role of STAT3 having been widely demonstrated, an increasing amount of data indicate that STAT3 functions are multifaced and not easy to classify. In fact, the specific cellular role of STAT3 seems to be determined by the integration of multiple signals, by the oncogenic environment, and by the alternative splicing into two distinct isoforms, STAT3α and STAT3β. On the basis of these different conditions, STAT3 can act both as a potent tumor promoter or tumor suppressor factor. This implies that the therapies based on STAT3 modulators should be performed considering the pleiotropic functions of this transcription factor and tailored to the specific tumor type.

Keywords: STAT3; cancer; tumor promoter; tumor suppressor.

Figure 1

Structure of signal transducer and activator of transcription 3 (STAT3). Functional domains: ND, NH2-terminal domain; CCD, coiled-coil domain; DBD, DNA-binding domain; LK, linker domain; SH2, Src homology 2 domain; TAD, transactivation domain. STAT3 activation is dependent on the phosphorylation (P) of a tyrosine residue Y705, which is located between the SH2 domain and TAD. Phosphorylation on serine (S) 727 is required for maximal transcriptional activity. After cytokine treatment, STAT3 is acetylated (Ac) on lysine (K) K87 and 685. Other post-translational modifications are di-methylation (di-Me) of K49, monoubiquitination of K97, and methylation (Me) of K140 and K180.

Figure 2

STAT3 upregulation and downregulation of factors involved in cell growth, apoptosis, angiogenesis, invasion, metastasis, and the immune system. STAT3 is activated through the interaction of cytokines and growth factors. Non-receptor tyrosine kinases have intrinsic kinase activity, whereas the receptors of ligands have associated JAK, which, when phosphorylated, acts as a platform for un-phosphorylated STAT3 to become activated. Phosphorylated STAT3 dimers translocate to the nucleus where they upregulate and downregulate a variety of genes that can contribute to tumorigenesis.

Figure 3

STAT3 inhibitors.