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Molecular Cancer
Published in: Molecular Cancer 1/2014

Open Access 01-12-2014 | Research

Inhibition of STAT3 dimerization and acetylation by garcinol suppresses the growth of human hepatocellular carcinoma in vitro and in vivo

Authors: Gautam Sethi, Snehajyoti Chatterjee, Peramaiyan Rajendran, Feng Li, Muthu K Shanmugam, Kwong Fai Wong, Alan Prem Kumar, Parijat Senapati, Amit K Behera, Kam Man Hui, Jeelan Basha, Nagashayana Natesh, John M Luk, Tapas K Kundu

Published in: Molecular Cancer | Issue 1/2014

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Abstract

Background

Constitutive activation of signal transducer and activator of transcription 3 (STAT3) has been linked with proliferation, survival, invasion and angiogenesis of a variety of human cancer cells, including hepatocellular carcinoma (HCC). Thus, novel agents that can suppress STAT3 activation have potential for both prevention and treatment of HCC. Here we report, garcinol, a polyisoprenylated benzophenone, could suppress STAT3 activation in HCC cell lines and in xenografted tumor of HCC in nude mice model.

Experimental design

Different HCC cell lines have been treated with garcinol and the inhibition of STAT3 activation, dimerization and acetylation have been checked by immunoblotting, immuno-fluorescence, and DNA binding assays. Xenografted tumor model has been generated in nude mice using HCC cell line and effect of garcinol in the inhibition of tumor growth has been investigated.

Results

Garcinol could inhibit both constitutive and interleukin (IL-6) inducible STAT3 activation in HCC cells. Computational modeling showed that garcinol could bind to the SH2 domain of STAT3 and suppress its dimerization in vitro. Being an acetyltransferase inhibitor, garcinol also inhibits STAT3 acetylation and thus impairs its DNA binding ability. The inhibition of STAT3 activation by garcinol led to the suppression of expression of various genes involved in proliferation, survival, and angiogenesis. It also suppressed proliferation and induced substantial apoptosis in HCC cells. Remarkably, garcinol inhibited the growth of human HCC xenograft tumors in athymic nu/nu mice, through the inhibition of STAT3 activation.

Conclusion

Overall, our results suggest that garcinol exerts its anti-proliferative and pro-apoptotic effects through suppression of STAT3 signaling in HCC both in vitro and in vivo.
Appendix
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Metadata
Title
Inhibition of STAT3 dimerization and acetylation by garcinol suppresses the growth of human hepatocellular carcinoma in vitro and in vivo
Authors
Gautam Sethi
Snehajyoti Chatterjee
Peramaiyan Rajendran
Feng Li
Muthu K Shanmugam
Kwong Fai Wong
Alan Prem Kumar
Parijat Senapati
Amit K Behera
Kam Man Hui
Jeelan Basha
Nagashayana Natesh
John M Luk
Tapas K Kundu
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2014
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/1476-4598-13-66

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