Honokiol inhibits signal transducer and activator of transcription-3 signaling, proliferation, and survival of hepatocellular carcinoma cells via the protein tyrosine phosphatase SHP-1
Honokiol inhibits signal transducer and activator of transcription-3 signaling, proliferation, and survival of hepatocellular carcinoma cells via the protein tyrosine phosphatase SHP-1
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DOI：
10.1002/jcp.22954
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发表时间：
2012-05-01
影响因子：
5.6
通讯作者：
Sethi, Gautam
中科院分区：
文献类型：
--
作者：
Rajendran, Peramaiyan;Li, Feng;Sethi, Gautam
信号转导子和转录激活子3（STAT 3）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，是一个有吸引力的治疗靶点。在本报告中，我们研究了和诺啡肽是否通过干扰STAT 3激活途径介导其作用。利用功能蛋白质组学肿瘤通路技术平台和不同的HCC细胞系，研究和厚朴对STAT 3激活、相关蛋白激酶和磷酸酶、STAT 3调节的基因产物和凋亡的影响。我们发现，honoklatin抑制组成型和诱导型STAT 3的激活在HCC细胞中的剂量和时间依赖性的方式。这种抑制是通过抑制上游激酶c-Src、Janus激活激酶1和Janus激活激酶2的激活来介导的。钒酸盐处理逆转和厚朴酚诱导的STAT 3下调，表明酪氨酸磷酸酶的参与。事实上，我们发现和厚朴诱导酪氨酸磷酸酶SHP-1的表达，这与组成性STAT 3激活的下调相关。此外，通过siRNA缺失SHP-1基因消除了和诺啡肽抑制STAT 3活化的能力。和诺昔康对STAT 3激活的抑制导致参与增殖、存活和血管生成的各种基因产物的抑制。最后，和厚朴酚抑制增殖，并显着增强紫杉醇和阿霉素在肝癌细胞中的凋亡作用。总的来说，这些结果表明，honoklastine是一种新型的STAT 3激活阻断剂，可能对治疗HCC和其他癌症具有巨大的潜力。J.细胞。227：21842195，2012。(C)2011 Wiley Periodicals，Inc.
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. J. Cell. Physiol. 227: 21842195, 2012. (C) 2011 Wiley Periodicals, Inc.