Ascochlorin, an isoprenoid antibiotic inhibits growth and invasion of hepatocellular carcinoma by targeting STAT3 signaling cascade through the induction of PIAS3
Ascochlorin, an isoprenoid antibiotic inhibits growth and invasion of hepatocellular carcinoma by targeting STAT3 signaling cascade through the induction of PIAS3
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DOI：
10.1016/j.molonc.2014.12.008
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发表时间：
2015-04-01
影响因子：
6.6
通讯作者：
Sethi, Gautam
中科院分区：
文献类型：
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作者：
Dai, Xiaoyun;Ahn, Kwang Seok;Sethi, Gautam
信号转导和转录激活因子3(STAT3)等癌基因转录因子的失控激活在肝细胞癌的增殖和生存中起着关键作用。因此，能够抑制STAT3激活的药物可能在治疗肝癌患者方面具有巨大的潜力。因此，在本报告中，我们研究了异戊二烯类抗生素抗坏血酸(ASC)对不同肝癌细胞系和原位小鼠模型中STAT3激活级联反应的影响。我们观察到ASC可以显著抑制原始性和IL-6/EGF诱导的STAT3激活，并降低其与DNA的结合能力。ASC可上调活化STAT3蛋白抑制因子(PIAS3)的表达，PIAS3可与STAT3DNA结合域结合，从而下调STAT3的激活。SiRNA缺失PIAS3基因后，ASC抑制STAT3活化和诱导肝癌细胞凋亡的能力消失。ASC还调节STAT3调节的多种致癌基因产物的表达。最后，当在腹膜内给药时，ASC也抑制了原位肝癌小鼠模型中的肿瘤生长，并减少了肿瘤组织中STAT3的激活。总之，我们的研究结果表明，ASC主要通过抑制STAT3信号级联途径发挥抗肿瘤作用，可以为肝癌患者的新型治疗奠定基础。(C)2014年欧洲生化学会联合会。爱思唯尔出版，版权所有。
Deregulated activation of oncogenic transcription factors such as signal transducer and activator of transcription 3 (STAT3) plays a pivotal role in proliferation and survival of hepatocellular carcinoma (HCC). Thus, agents which can inhibit STAT3 activation may have an enormous potential for treatment of HCC patients. Hence, in the present report, we investigated the effect of ascochlorin (ASC), an isoprenoid antibiotic on STAT3 activation cascade in various HCC cell lines and orthotopic mouse model. We observed that ASC could substantially inhibit both constitutive and IL-6/EGF inducible STAT3 activation as well as reduce its DNA binding ability. ASC increased the expression of protein inhibitor of activated STAT3 (PIAS3) which could bind to STAT3 DNA binding domain and thereby down-regulate STAT3 activation. Deletion of PIAS3 gene by siRNA abolished the ability of ASC to inhibit STAT3 activation and induce apoptosis in HCC cells. ASC also modulated the expression of diverse STAT3-regulated oncogenic gene products. Finally, when administered intraperitoneally, ASC also inhibited tumor growth in an orthotopic HCC mouse model and reduced STAT3 activation in tumor tissues. Overall our results indicate that ASC mediates its anti-tumor effects predominantly through the suppression of STAT3 signaling cascade, and can form the basis of novel therapy for HCC patients. (C) 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.