Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 289, Issue 49, Pages 34296-34307Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M114.601104
Keywords
Bioinformatics; Cell Migration; Hepatocellular Carcinoma; Janus Kinase (JAK); STAT3
Categories
Funding
- University Grants Commission [41-257-2012-SR]
- Vision Group Science and Technology, Department of Science and Technology [SR/FT/LS-142/2012]
- National Medical Research Council of Singapore
- Academic Research Fund Tier 1
- National University Health System Bench-to-Bedside and Bench-to-Bedside-to-Product Grant
- Department of Science and Technology (DST)-INSPIRE fellowship
- University Grants Commission-Basic Scientific Research fellowship
- European Research Commission
- DST-Japan Society for the Promotion of Science [DST/INT/JAP/P-79/09]
- DST-Korea [INT/Indo-Korea/122/2011-12]
- Institution of Excellence (IOE) grants from the University of Mysore
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Background: Constitutive activation of STAT3 is associated with the progression of hepatocellular carcinoma (HCC), and abrogation of STAT3 signaling is a potential target for HCC treatment. Results: A novel azaspirane modulates the JAK-STAT pathway in HCC. Conclusion: The lead compound induces apoptosis by down-regulating STAT3 signaling. Significance: This investigation reports a novel inhibitor of the JAK-STAT pathway with the potential to target various cancers. Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that regulates genes involved in cell growth, proliferation, and survival, and given its association with many types of cancers, it has recently emerged as a promising target for therapy. In this work, we present the synthesis of N-substituted azaspirane derivatives and their biological evaluation against hepatocellular carcinoma (HCC) cells (IC50 = 7.3 m), thereby identifying 2-(1-(4-(2-cyanophenyl)1-benzyl-1H-indol-3-yl)-5-(4-methoxy-phenyl)-1-oxa-3-azaspiro(5,5) undecane (CIMO) as a potent inhibitor of the JAK-STAT pathway with selectivity over normal LO2 cells (IC50 > 100 m). The lead compound, CIMO, suppresses proliferation of HCC cells and achieves this effect by reducing both constitutive and inducible phosphorylation of JAK1, JAK2, and STAT3. Interestingly, CIMO displayed inhibition of Tyr-705 phosphorylation, which is required for nuclear translocation of STAT3, but it has no effect on Ser-727 phosphorylation. CIMO accumulates cancer cells in the sub-G(1) phase and decreases STAT3 in the nucleus and thereby causes down-regulation of genes regulated via STAT3. Suppression of STAT3 phosphorylation by CIMO and knockdown of STAT3 mRNA using siRNA transfection displayed a similar effect on the viability of HCC cells. Furthermore, CIMO significantly decreased the tumor development in an orthotopic HCC mouse model through the modulation of phospho-STAT3, Ki-67, and cleaved caspase-3 in tumor tissues. Thus, CIMO represents a chemically novel and biologically in vitro and in vivo validated compound, which targets the JAK-STAT pathway as a potential cancer treatment.
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