Positive Health Online

Abstract

RAJENDRAN and COLLEAGUES, Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore Cancer Science Institute of Singapore, National University of Singapore, Singapore investigated whether the apoptotic, antiproliferative and chemosensitizing effects of gamma-tocotrienol are associated with its ability to suppress STAT3 activation in hepatocellular carcinoma (HCC).

Background

Activation of signal transducer and activator of transcription 3 (STAT3) play a critical role in the survival, proliferation, angiogenesis and chemoresistance of tumour cells. Thus, agents that suppress STAT3 phosphorylation have potential as cancer therapies. In the present study, the authors investigated whether the apoptotic, antiproliferative and chemosensitizing effects of gamma-tocotrienol are associated with its ability to suppress STAT3 activation in hepatocellular carcinoma (HCC).

Methodology

The effect of gamma-tocotrienol on STAT3 activation, associated protein kinases and phosphatase, STAT3-regulated gene products, cellular proliferation and apoptosis in HCC cells was investigated.

Results

gamma-Tocotrienol inhibited both the constitutive and inducible activation of STAT3 with minimum effect on STAT5. gamma-Tocotrienol also inhibited the activation of Src, JAK1 and JAK2 implicated in STAT3 activation. Pervanadate reversed the gamma-tocotrienol-induced down-regulation of STAT3, suggesting the involvement of a protein tyrosine phosphatase. Indeed, we found that gamma-tocotrienol induced the expression of the tyrosine phosphatase SHP-1 and deletion of the SHP-1 gene by small interfering RNA abolished the ability of gamma-tocotrienol to inhibit STAT3 activation. gamma-Tocotrienol also down-regulated the expression of STAT3-regulated gene products, including cyclin D1, Bcl-2, Bcl-xL, survivin, Mcl-1 and vascular endothelial growth factor. Finally, gamma-tocotrienol inhibited proliferation, induced apoptosis and significantly potentiated the apoptotic effects of chemotherapeutic drugs (paclitaxel and doxorubicin) used for the treatment of HCC.

Conclusion

Overall, these results suggest that gamma-tocotrienol is a novel blocker of the STAT3 activation pathway, with a potential role in future therapies for HCC and other cancers.

References

Rajendran P, Li F, Manu KA, Shanmugam MK, Loo SY, Kumar AP and Sethi G. gamma-Tocotrienol is a novel inhibitor of constitutive and inducible STAT3 signalling pathway in human hepatocellular carcinoma: potential role as an antiproliferative, pro-apoptotic and chemosensitizing agent. British Journal of Pharmacology. 163(2):283-98. May 2011. Other ID Source: NLM. PMC3087132 [Available on 05/01/12].

Comment

The above research details, at the molecular level, the modulation of the STAT3 group of transcription factors which play a role in many systems, including the survival, proliferation, angiogenesis and chemoresistance of tumour cells. The results demonstrate that gamma-tocotrienol - a member of the vitamin E family - induced apoptosis (cell suicide) and potentiated the apoptotic effects of chemotherapy drugs, thus suggesting that gamma-tocotrienol could play a role in hepatic [liver] cancer therapy.