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

Molecular Cancer

Research

Nagashayana Natesh¹  Muthu K Shanmugam²  Peramaiyan Rajendran²  Feng Li²  Kwong Fai Wong³  Gautam Sethi³  John M Luk⁴  Alan Prem Kumar⁵  Kam Man Hui⁶  Amit K Behera⁷  Tapas K Kundu⁷  Jeelan Basha⁷  Snehajyoti Chatterjee⁷  Parijat Senapati⁷ 

[1] Central Government Health Scheme Dispensary, No. 3, Basavanagudi, Bangalore, India;Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore, Singapore;Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore, Singapore;Cancer Science Institute of Singapore, National University of Singapore, 117456, Singapore, Singapore;Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore, Singapore;Cancer Science Institute of Singapore, National University of Singapore, 117456, Singapore, Singapore;Institute of Molecular and Cell Biology, 61 Biopolis Drive, 138673, Proteos, Singapore, Singapore;Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore, Singapore;Cancer Science Institute of Singapore, National University of Singapore, 117456, Singapore, Singapore;School of Biomedical Sciences, Faculty of Health Sciences, Curtin University, 6009, Bentley, WA, Australia;Department of Biological Sciences, University of North Texas, 76203, Denton, TX, USA;Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, 169610, Singapore, Singapore;Jawaharlal Nehru Centre for Advanced Scientific Research, Molecular Biology and Genetics Unit, Transcription and Disease Laboratory, Jakkur P.O., 560064, Bangalore, India;

关键词: HCC;    STAT3;    Acetylation;    Garcinol;    Apoptosis;   

DOI  :  10.1186/1476-4598-13-66

 received in 2013-08-15, accepted in 2014-03-12,  发布年份 2014

来源: Springer

【 摘 要 】

BackgroundConstitutive 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 designDifferent 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.ResultsGarcinol 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.ConclusionOverall, 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.

【 授权许可】

Unknown   
© Sethi et al.; licensee BioMed Central Ltd. 2014. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.