Inhibition of STAT3 dimerization and acetylation by garcinol suppresses the growth of human hepatocellular carcinoma in vitro and in vivo
Access Status
Authors
Date
2014Type
Metadata
Show full item recordCitation
Source Title
ISSN
School
Remarks
This open access article is distributed under the Creative Commons license http://creativecommons.org/licenses/by/2.0/
Collection
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.
Related items
Showing items related by title, author, creator and subject.
-
Shanmugam, M.; Rajendran, P.; Li, F.; Nema, T.; Vali, S.; Abbasi, T.; Kapoor, S.; Sharma, A.; Kumar, Alan Prem; Ho, P.; Hui, K.; Sethi, G. (2011)Activation of transcription factors nuclear factor-κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) is frequently observed in prostate cancer and has been linked with tumor cell proliferation, ...
-
Rajendran, P.; Li, F.; Shanmugam, M.; Vali, S.; Abbasi, T.; Kapoor, S.; Ahn, K.; Kumar, Alan Prem; Sethi, G. (2012)The activation of signal transducers and activators of transcription 3 (STAT3) has been closely linked with the proliferation, survival, invasion, and angiogenesis of hepatocellular carcinoma (HCC) and represents an ...
-
Shanmugam, M.; Rajendran, P.; Li, F.; Kim, C.; Sikka, S.; Siveen, K.; Kumar, Alan Prem; Ahn, K.; Sethi, G. (2015)Persistent activation of signal transducer and activator of transcription 3 (STAT3) is one of the characteristic features of renal cell carcinoma (RCC) and often linked to its deregulated proliferation, survival, and ...