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.
Br J Pharmacol. 2011 May;163(2):283-98. doi: 10.1111/j.1476-5381.2010.01187.x.
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, we investigated whether the apoptotic, antiproliferative and chemosensitizing effects of γ-tocotrienol are associated with its ability to suppress STAT3 activation in hepatocellular carcinoma (HCC).
The effect of γ-tocotrienol on STAT3 activation, associated protein kinases and phosphatase, STAT3-regulated gene products, cellular proliferation and apoptosis in HCC cells was investigated.
γ-Tocotrienol inhibited both the constitutive and inducible activation of STAT3 with minimum effect on STAT5. γ-Tocotrienol also inhibited the activation of Src, JAK1 and JAK2 implicated in STAT3 activation. Pervanadate reversed the γ-tocotrienol-induced down-regulation of STAT3, suggesting the involvement of a protein tyrosine phosphatase. Indeed, we found that γ-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 γ-tocotrienol to inhibit STAT3 activation. γ-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, γ-tocotrienol inhibited proliferation, induced apoptosis and significantly potentiated the apoptotic effects of chemotherapeutic drugs (paclitaxel and doxorubicin) used for the treatment of HCC.
Overall, these results suggest that γ-tocotrienol is a novel blocker of the STAT3 activation pathway, with a potential role in future therapies for HCC and other cancers.
信号转导子和转录激活子 3（STAT3）的激活在肿瘤细胞的存活、增殖、血管生成和化疗耐药中起着关键作用。因此，抑制 STAT3 磷酸化的药物具有作为癌症治疗药物的潜力。在本研究中，我们研究了γ-生育三烯酚是否通过抑制 STAT3 激活来发挥其对肝癌（HCC）的凋亡、抗增殖和化疗增敏作用。
研究了γ-生育三烯酚对 HCC 细胞中 STAT3 激活、相关蛋白激酶和磷酸酶、STAT3 调节的基因产物、细胞增殖和凋亡的影响。
γ-生育三烯酚抑制了 STAT3 的组成性和诱导性激活，对 STAT5 的影响最小。γ-生育三烯酚还抑制了 Src、JAK1 和 JAK2 的激活，这些激酶参与了 STAT3 的激活。过钒酸钠逆转了γ-生育三烯酚诱导的 STAT3 下调，表明涉及一种蛋白酪氨酸磷酸酶。事实上，我们发现γ-生育三烯酚诱导了酪氨酸磷酸酶 SHP-1 的表达，并且通过小干扰 RNA 敲除 SHP-1 基因消除了γ-生育三烯酚抑制 STAT3 激活的能力。γ-生育三烯酚还下调了 STAT3 调节的基因产物的表达，包括细胞周期蛋白 D1、Bcl-2、Bcl-xL、存活素、Mcl-1 和血管内皮生长因子。最后，γ-生育三烯酚抑制增殖，诱导凋亡，并显著增强用于治疗 HCC 的化疗药物（紫杉醇和多柔比星）的凋亡作用。
总的来说，这些结果表明，γ-生育三烯酚是 STAT3 激活途径的一种新型阻断剂，在未来 HCC 和其他癌症的治疗中具有潜在作用。
