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STAT3 As a Target for Inducing Apoptosis in Solid and Hematological Tumors Khandaker Al Zaid Siddiquee1, James Turkson1

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STAT3 As a Target for Inducing Apoptosis in Solid and Hematological Tumors Khandaker Al Zaid Siddiquee1, James Turkson1 npg STAT3 as anticancer drug target 254 Cell Research (2008) 18:254-267. npg © 2008 IBCB, SIBS, CAS All rights reserved 1001-0602/08 $ 30.00 REVIEW www.nature.com/cr STAT3 as a target for inducing apoptosis in solid and hematological tumors Khandaker Al Zaid Siddiquee1, James Turkson1 1Biomolecular Science Center and Department of Molecular Biology and Microbiology, Burnett School of Biomedical Sciences, University of Central Florida College of Medicine, Orlando, FL 32826, USA 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 sup- porting 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. Keywords: STAT3, DNA-binding, apoptosis, small-molecule inhibitors, cell growth, human tumors Cell Research (2008) 18:254-267. doi: 10.1038/cr.2008.18; published online 29 January 2008 Introduction functions as the transcriptional activation domain [1, 2]. The STAT proteins are differentially activated in a Signal Transducer and Activator of Transcription 3 context-dependent manner in response to growth factors, (STAT3) belongs to the STAT family of proteins, which are cytokines, or other polypeptide ligands. They have impor- both signal transducers and transcription factors. At least tant roles in fundamental processes, including proliferation, seven members in this family have been identified, namely, development, differentiation, inflammation, and apoptosis. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STATs activation is initiated by the phosphorylation on a STAT6, which are encoded by distinct genes. Alternative critical tyrosyl residue. Upon the binding of growth factors splicing also gives rise to naturally occurring truncated or cytokines to their cognate receptors on the cell surface, forms of some of the STAT proteins, such as STAT1β STATs are recruited to the cytoplasmic portions of the re- and STAT3β, which are splice variants of the wild-type, ceptors, where they become phosphorylated on a critical full-length STAT1 and STAT3 proteins, respectively, with tyrosyl residue (Y) in the C-terminus by Tyr kinases of deletions of the C-terminal domains. Structurally, STAT growth factor receptors, or by cytoplasmic, non-receptor proteins have the following distinct domains: the N-termi- Tyr kinases, including Src, Janus kinases (Jaks) or Abel- nal, coiled-coil, DNA binding, the Linker, Src-homology 2 son (Abl) kinase (Figures 1 and 2). In the transactivation (SH2) and C-terminal transactivation domains (Figure 1). domain of some STAT proteins is a serine residue (S) Each of these domains has a distinct function. For example, (Figure 1), the phosphorylation of which maximizes the the N-terminal domain is important in STAT dimer-dimer transcriptional activity of these proteins [3]. Tyrosine- interactions; the DNA binding domain forms complexes phosphorylated STATs then dimerize through reciprocal between STAT proteins and DNA; the SH2 domain engages pTyr-SH2 domain interactions, translocate into the nucleus in dimerization between two activated STAT monomers and bind to specific STAT-response elements in the pro- through reciprocal phospho-tyrosine (pTyr)-SH2 domain moters of target genes, thereby inducing the transcription interactions, while the C-terminal portion of the protein of those genes essential for their physiological functions. Under normal biological conditions, STATs activation is rapid and transient. However, aberrant activation of certain STAT proteins, particularly STAT3 and STAT5, is Correspondence: James Turkson Tel: +1 407 882 2441; Fax: +1 407 384 2062 associated with many human cancers (for a comprehensive E-mail: [email protected] review, see [4-11]). Cell Research | Vol 18 No 2 | February 2008 Khandaker Al Zaid Siddiquee and James Turkson npg 255 Aberrant STAT3 and malignant transformation porting STAT3 as an oncogene by showing that expres- sion of an artificially engineered, constitutively dimerized Constitutive activation of STAT3 was first observed STAT3C alone was sufficient to transform normal mouse associated with oncogenic transformation by the viral Src fibroblasts, and that the STAT3C-transformed cells were oncoprotein [12]. A similar observation was subsequently able to form tumors in nude mice [27]. also reported for transformation by other oncogenic Tyr Compelling evidence has now established that aberrant kinases, such as v-Ros, v-Fps, Etk/BMX, v-Abl, and STAT3 is a molecular abnormality that has a critical role Lck [13-18], or by viruses/viral proteins that directly or in the development and progression of human tumors. In indirectly activate Tyr kinase pathways, including human that regard, many human solid and hematological tumors T lymphotropic virus (HTLV)-1, polyomavirus middle T harbor constitutively active STAT3 [7, 8, 10, 11]. A variety antigen, Epstein-Barr virus (EBV) and herpes virus saimiri of molecular causes contribute to promoting constitutive [16, 19-24]. Subsequent genetic and molecular evidence STAT3 activation in malignant cells. In the absence of indicated that aberrant STAT3 is a necessary requirement any known naturally occurring activating mutations in the for malignant transformation [25, 26]. These studies were stat3 gene, aberrant STAT3 activation is predominantly followed by another that provided genetic evidence sup- due to persistent Tyr phosphorylation signals emanating N-terminal Coiled-coil DNA-binding Linker SH2 Transactivation NH2 Y S COOH 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-ter- minal transactivation domain of some STAT proteins and is phosphorylated to enhance transcriptional activity. NH2, amino (N) terminus; COOH, carboxy (C) terminus. Growth factor Cytokine receptors receptors Non-receptor RTK RTK R R tyrosine kinases Extracellular Jak Src Src Src Jak P P P Abl P P P STAT3 STAT3P P STAT3P P Plasma STAT3 STAT3 Membrane STAT3 STAT3 P Cytoplasmic STAT3 P P STAT3 Gene Nuclear Transcription STAT3 P 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 se- quences. www.cell-research.com | Cell Research npg STAT3 as anticancer drug target 256 from dysregulated upstream Tyr kinases, such as hyperac- of host immune surveillance (Figure 3) [8, 10, 11, 42]. At tive growth factor receptors or non-receptor Tyr kinases, the molecular level, evidence indicates that aberrant STAT3 including Src or Jaks, or the result of over-expression of causes expression changes of critical genes that dysregulate stimulatory ligands, such as EGF or IL-6 [25, 28-36]). cell cycle and cell growth. Studies in transformed cells and These molecular events are exemplified by the persistent using both solid and hematological tumor cells in vitro and stimulation of the IL-6/gp130 and the Jak/STAT pathway in vivo, including HNSCC, NSCLC, glioma and breast in multiple myeloma (MM), large granular lymphocyte cancers, show that constitutive activation of STAT3 is as- (LGL) leukemia, and prostate cancer [28, 37, 38], and by sociated with the induction of Cyclin D1/Cyclin D2 and the elevated EGFR-mediated signaling, as well as Src and c-Myc expression, and down-regulation of expression of Jak kinases activities in breast cancer, prostate cancer, non- the cyclin-dependent kinase inhibitor, p21WAF (see [4-11, small cell lung cancer (NSCLC), melanoma, pancreatic 43] for extensive reviews). cancer, and head and neck squamous carcinoma (HNSCC) Moreover, evidence indicates that abnormal STAT3 cells [16, 29-31, 34-36, 39-41], which result in constitu- activity promotes tumorigenesis in part by up-regulating tive STAT3 activation. While the molecular and biological the expression of antiapoptotic proteins, such as Bcl-xL/ mechanisms by which persistently activated STAT3 medi- Bcl-2, and Mcl-1 [28, 37, 44, 45]. Thus, the expression of ates cancer formation continue to be investigated, available the artificially designed, constitutively dimerized STAT3C evidence strongly supports the role of aberrant STAT3 in alone induced the expression of Bcl-xL in transformed the promotion of uncontrolled cell proliferation and growth, cells
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