title: Targeting the STAT3 signaling pathway in cancer: role of synthetic and natural inhibitors.
abstract: Signal transducers and activators of transcription (STATs) comprise a family of cytoplasmic transcription factors that mediate intracellular signaling that is usually generated at cell surface receptors and thereby transmit it to the nucleus. Numerous studies have demonstrated constitutive activation of STAT3 in a wide variety of human tumors, including hematological malignancies (leukemias, lymphomas, and multiple myeloma) as well as diverse solid tumors (such as head and neck, breast, lung, gastric, hepatocellular, colorectal and prostate cancers). There is strong evidence to suggest that aberrant STAT3 signaling promotes initiation and progression of human cancers by either inhibiting apoptosis or inducing cell proliferation, angiogenesis, invasion, and metastasis. Suppression of STAT3 activation results in the induction of apoptosis in tumor cells, and accordingly its pharmacological modulation by tyrosine kinase inhibitors, antisense oligonucleotides, decoy nucleotides, dominant negative proteins, RNA interference and chemopreventive agents have been employed to suppress the proliferation of various human cancer cells in culture and tumorigenicity in vivo. However, the identification and development of novel drugs that can target deregulated STAT3 activation effectively remains an important scientific and clinical challenge. This review presents the evidence for critical roles of STAT3 in oncogenesis and discusses the potential for development of novel cancer therapies based on mechanistic understanding of STAT3 signaling cascade.
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Kodappully Sivaraman
authors.initials: KS
authors.lastname: Siveen
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore.
authors.forename: Sakshi
authors.initials: S
authors.lastname: Sikka
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore.
authors.forename: Rohit
authors.initials: R
authors.lastname: Surana
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Dai
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Jingwen
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore; School of Biomedical Sciences, Faculty of Health Sciences, Curtin University, Western Australia, Australia; Department of Biological Sciences, University of North Texas, Denton, TX, USA.
authors.forename: Alan Prem
authors.initials: AP
authors.lastname: Kumar
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Benny K H
authors.initials: BK
authors.lastname: Tan
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore. Electronic address: phcgs@nus.edu.sg.
authors.forename: Gautam
authors.initials: G
authors.lastname: Sethi
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, American University of Health Sciences, Signal Hill, CA, USA. Electronic address: abishayee@auhs.edu.
authors.forename: Anupam
authors.initials: A
authors.lastname: Bishayee
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D063646:Carcinogenesis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D058990:Molecular Targeted Therapy; D009361:Neoplasm Invasiveness / Q000235:genetics*; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D054852:Small Molecule Libraries / Q000627:therapeutic use
chemical_list: D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D054852:Small Molecule Libraries
keywords: Inflammation; Inhibitors; Metastasis; Proliferation; STAT3; Tumorigenesis