Abstract 4711: Targeted inhibition of STAT3 dimerization by garcinol suppresses the growth of human hepatocellular carcinoma in vitro and in vivo.

Abstract

Abstract Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide and the third cause of global cancer mortality. Activation of signal transducer and activator of transcription 3 (STAT3) is commonly encountered in tumor cells and is a critical mediator of oncogenic signaling in HCC and controls the expression of several genes involved in proliferation, survival, metastasis and angiogenesis. Current drug-targeted therapies, besides being expensive, are associated with serious side effects and morbidity. Thus, novel agents that can suppress STAT3 activation have potential for both prevention and treatment of HCC. In the present report, we investigated whether the potent HAT/KAT inhibitor, garcinol, (a polyisoprenylated benzophenone), could suppress STAT3 activation in HCC cells and nude mice model. We found that garcinol could inhibit constitutive STAT3 activation in a dose- and time-dependent manner both by inhibiting STAT3 phosphorylation and acetylation in HCC cells. When investigated for molecular mechanism(s), we found that garcinol interferes with the dimer formation of STAT3 thereby inhibits its nuclear localization. Computational modeling showed that garcinol could bind to the SH2 domain of STAT3 and suppresses its dimerization in vitro. To understand the cellular mechanism(s) of inhibition of STAT3 function by garcinol, we observed that upon inhibition of STAT3 dimerization by garcinol, STAT3 DNA binding ability gets repressed. The inhibition of STAT3 activation by garcinol led to the suppression of various gene products involved in proliferation, survival, and angiogenesis. Finally, when administered i.p., garcinol inhibited the growth of human HCC xenograft tumors in male athymic nu/nu mice. In conclusion, results from in vitro and in vivo studies suggest that garcinol exerts its anti-proliferative and pro-apoptotic effects through suppression of STAT3 signaling cascade in HCC by inhibiting its phosphorylation, acetylation and ultimately dimerization. Citation Format: Muthu K. Shanmugam, Snehajyoti Chatterjee, Rajendran Peramaiyan, Feng Li, Parijat Senapati, Kwong Fai Wong, Kwong Fai Wong, Alan Prem Kumar, Alan Prem Kumar, Alan Prem Kumar, John M. Luk, John M. Luk, John M. Luk, Kam M. Hui, Kam M. Hui, Gautam Sethi, Gautam Sethi, Tapas K. Kundu. Targeted inhibition of STAT3 dimerization by garcinol suppresses the growth of human hepatocellular carcinoma in vitro and in vivo. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4711. doi:10.1158/1538-7445.AM2013-4711