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. 2020 Feb 10;43(1):e20180160.
doi: 10.1590/1678-4685-GMB-2018-0160. eCollection 2020.

Targeting STAT-3 signaling pathway in cancer for development of novel drugs: Advancements and challenges

Sundas Arshad  1 , Muhammad Naveed  2 , Mahad Ullia  3 , Khadija Javed  3 , Ayesha Butt  3 , Masooma Khawar  3 , Fazeeha Amjad  3
Affiliations

Targeting STAT-3 signaling pathway in cancer for development of novel drugs: Advancements and challenges

Sundas Arshad et al. Genet Mol Biol. .

Abstract

Signal transducers and activators of transcription 3 (STAT-3) is a transcription factor that regulates the gene expression of several target genes. These factors are activated by the binding of cytokines and growth factors with STAT-3 specific receptors on cell membrane. Few years ago, STAT-3 was considered an acute phase response element having several cellular functions such as inflammation, cell survival, invasion, metastasis and proliferation, genetic alteration, and angiogenesis. STAT-3 is activated by several types of inflammatory cytokines, carcinogens, viruses, growth factors, and oncogenes. Thus, the STAT3 pathway is a potential target for cancer therapeutics. Abnormal STAT-3 activity in tumor development and cellular transformation can be targeted by several genomic and pharmacological methodologies. An extensive review of the literature has been conducted to emphasize the role of STAT-3 as a unique cancer drug target. This review article discusses in detail the wide range of STAT-3 inhibitors that show antitumor effects both in vitro and in vivo. Thus, targeting constitutive STAT-3 signaling is a remarkable therapeutic methodology for tumor progression. Finally, current limitations, trials and future perspectives of STAT-3 inhibitors are also critically discussed.

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Figures

Figure 1
Figure 1. STAT-3 protein is segmental in organization. It contains an N-terminus domain (ND), coiled-coil domain (CCD), DNA-binding domain (DBD), Src homology 2 (SH2) domain, linker domain, Tyr (Y) residue, and the transactivation domain (TAD).
Figure 2
Figure 2. Polypeptides bind to their associated receptors and trigger the tyrosine (Tyr) kinase (TK) events of the receptors, Src or JAKs. Underlying STAT-3 action is the stimulated receptor for phosphorylation on specific Tyr residue by TKs that causes STAT-3:STAT-3 dimerization and stimulation. STAT-3 mounts up in the nucleus, where it binds to specific DNA response elements in the promoters of target genes, which causes gene transcription.
Figure 3
Figure 3. Three dimensional structure of STAT 3 indicating its active and inhibitory sites. (a) 4Z1A PDB hit of STAT 3. (b) Different domains of STAT 3 present in loops of STAT 3.
See this image and copyright information in PMC

References

    1. Aggarwal BB, Kunnumakkara AB, Harikumar KB, Gupta SR, Tharakan ST, Koca C, Dey S, Sung B. Signal transducer and activator of transcription-3, inflammation, and cancer. Ann N Y Acad Sci. 2009;1171:59–76. - PMC - PubMed
    1. Ahn KS, Sethi G, Sung B, Goel A, Ralhan R, Aggarwal BB. Guggulsterone, a farnesoid X receptor antagonist, inhibits constitutive and inducible STAT3 activation through induction of a protein tyrosine phosphatase SHP-1. Cancer Res. 2008;68:4406–4415. - PubMed
    1. Ahsan H, Aziz MH, Ahmad N. Ultraviolet B exposure activates Stat3 signaling via phosphorylation at tyrosine 705 in skin of SKH1 hairless mouse: A target for the management of skin cancer? Biochem Biophys Res Commun. 2005;333:241–246. - PubMed
    1. Akira S, Nishio Y, Inoue M, Wang X-J, We S, Matsusaka T, Yoshida K, Sudo T, Naruto M, Kishimoto T. Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway. Cell. 1994;77:63–71. - PubMed
    1. Aoki Y, Feldman GM, Tosato G. Inhibition of STAT3 signaling induces apoptosis and decreases survivin expression in primary effusion lymphoma. Blood. 2003;101:1535–1542. - PubMed