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
|dc.contributor.author||Kumar, Alan Prem|
|dc.identifier.citation||Mohan, C. and Bharathkumar, H. and Bulusu, K. and Pandey, V. and Rangappa, S. and Fuchs, J. and Shanmugam, M. et al. 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.|
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 µM), thereby identifying 2-(1-(4-(2-cyanophenyl)1-benzyl-1Hindol-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<100µM). 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-G1 phase and decreases STAT3 in the nucleusand 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 JAKSTAT pathway as a potential cancer treatment.
|dc.publisher||American Society for Biochemistry and Molecular Biology Inc.|
|dc.title||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|
|dcterms.source.title||Journal of Biological Chemistry|
|curtin.department||School of Biomedical Sciences|
|curtin.accessStatus||Open access via publisher|
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