Development of a novel azaspirane that targets the Janus kinase-signal Transducer and Activator of Transcription (STAT) pathway in hepatocellular carcinoma in vitro and in vivo

Mohan, C. D. and Bharathkumar, H. and Bulusu, K. C. and Pandey, V. and Rangappa, S. and Fuchs, J. E. and Shanmugam, M. K. and Dai, X. and Li, F. and Deivasigamani, A. and Hui, K. M. and Prem Kumar, A. and Lobie, P. E. and Bender, A. and Basappa and Sethi, G. and Rangappa, K. S. (2014) Development of a novel azaspirane that targets the Janus kinase-signal Transducer and Activator of Transcription (STAT) pathway in hepatocellular carcinoma in vitro and in vivo. Journal of Biological Chemistry, 289 (49). pp. 34296-34307.

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Official URL: https://doi.org/10.1074/jbc.M114.601104

Abstract

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-ox a-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.

Item Type: Article
Uncontrolled Keywords: Bioinformatics; Cell Migration; Hepatocellular Carcinoma; Janus Kinase (JAK); STAT3
Subjects: C Chemical Science > Chemistry
Divisions: Department of > Chemistry
Depositing User: Arshiya Kousar
Date Deposited: 04 Jun 2019 05:00
Last Modified: 10 Jul 2019 05:46
URI: http://eprints.uni-mysore.ac.in/id/eprint/2105

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