Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
J Cell Physiol. 2012 May;227(5):2184-95. doi: 10.1002/jcp.22954.
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 attractive target for therapy. In the present report, we investigated whether honokiol mediates its effect through interference with the STAT3 activation pathway. The effect of honokiol on STAT3 activation, associated protein kinases, and phosphatase, STAT3-regulated gene products and apoptosis was investigated using both functional proteomics tumor pathway technology platform and different HCC cell lines. We found that honokiol inhibited both constitutive and inducible STAT3 activation in a dose- and time-dependent manner in HCC cells. The suppression was mediated through the inhibition of activation of upstream kinases c-Src, Janus-activated kinase 1, and Janus-activated kinase 2. Vanadate treatment reversed honokiol-induced down-regulation of STAT3, suggesting the involvement of a tyrosine phosphatase. Indeed, we found that honokiol induced the expression of tyrosine phosphatase SHP-1 that correlated with the down-regulation of constitutive STAT3 activation. Moreover, deletion of SHP-1 gene by siRNA abolished the ability of honokiol to inhibit STAT3 activation. The inhibition of STAT3 activation by honokiol led to the suppression of various gene products involved in proliferation, survival, and angiogenesis. Finally, honokiol inhibited proliferation and significantly potentiated the apoptotic effects of paclitaxel and doxorubicin in HCC cells. Overall, the results suggest that honokiol is a novel blocker of STAT3 activation and may have a great potential for the treatment of HCC and other cancers.
信号转导子和转录激活子 3（STAT3）的激活与肝细胞癌（HCC）的增殖、存活、侵袭和血管生成密切相关，是治疗的一个有吸引力的靶点。在本报告中，我们研究了厚朴酚是否通过干扰 STAT3 激活途径来发挥其作用。使用功能蛋白质组学肿瘤通路技术平台和不同的 HCC 细胞系，研究了厚朴酚对 STAT3 激活、相关蛋白激酶和磷酸酶、STAT3 调节的基因产物和凋亡的影响。我们发现厚朴酚以剂量和时间依赖的方式抑制 HCC 细胞中组成性和诱导性 STAT3 激活。抑制作用是通过抑制上游激酶 c-Src、Janus 激活激酶 1 和 Janus 激活激酶 2 的激活介导的。钒酸盐处理逆转了 honokiol 诱导的 STAT3 下调，表明涉及酪氨酸磷酸酶。事实上，我们发现 honokiol 诱导了酪氨酸磷酸酶 SHP-1 的表达，这与组成性 STAT3 激活的下调相关。此外，通过 siRNA 敲除 SHP-1 基因消除了 honokiol 抑制 STAT3 激活的能力。厚朴酚抑制 STAT3 激活导致参与增殖、存活和血管生成的各种基因产物的抑制。最后，厚朴酚抑制增殖，并显著增强紫杉醇和阿霉素在 HCC 细胞中的凋亡作用。总的来说，这些结果表明厚朴酚是 STAT3 激活的一种新型抑制剂，可能在治疗 HCC 和其他癌症方面具有很大的潜力。
