STAT3 as a target for inducing apoptosis in solid and hematological tumors

Abstract

Studies in the past few years have provided compelling evidence for the critical role of aberrant Signal Transducer and Activator of Transcription 3 (STAT3) in malignant transformation and tumorigenesis. Thus, it is now generally accepted that STAT3 is one of the critical players in human cancer formation and represents a valid target for novel anticancer drug design. This review focuses on aberrant STAT3 and its role in promoting tumor cell survival and supporting the malignant phenotype. A brief evaluation of the current strategies targeting STAT3 for the development of novel anticancer agents against human tumors harboring constitutively active STAT3 will also be presented.

Figure 1

A schematic representation of STAT protein structure. Linear representation of the domain structures of the STAT proteins. The critical tyrosyl residue (Y) is shown, the phosphorylation of which initiates STAT activation and the dimerization between two STAT monomers through a reciprocal pTyr-SH2 domain interactions. A serine (S) residue is present in the C-terminal transactivation domain of some STAT proteins and is phosphorylated to enhance transcriptional activity. NH₂, amino (N) terminus; COOH, carboxy (C) terminus.

Figure 2

Activation of the STAT signaling pathway. STAT activation is induced by the binding of ligands, such as growth factors and cytokines to their cognate receptors (R) on the cell surface, which initiates the phosphorylation of the critical tyrosyl residue of STATs by growth factor receptor Tyr kinases (RTKs) or by non-receptor Tyr kinases (NRTKs), such as Jaks, Src or Abelson (Abl) kinase. NRTKs can also directly phosphorylate STATs in the absence of ligand-binding to receptors. Tyr-phosphorylated and activated STAT monomers engage in reciprocal pTyr-SH2 domain interactions for dimerization, and the resulting dimers translocate to the nucleus to regulate the transcription of specific genes by binding to specific STAT-responsive promoter sequences.

Figure 3

Model of constitutive STAT3 activation and its role in oncogenesis. Aberrant signals from upstream growth factor RTKs, cytokine R, their overexpressed ligands, or activated NRTKs produce persistent Tyr kinase signals that induce constitutive STAT3 activation. Constitutive STAT3 activation results in dysregulation of cell cycle control and apoptosis genes, and genes that promote invasion, metastasis, and angiogenesis, and also leads to the suppression of host immune surveillance. These molecular changes together contribute to oncogenesis.