Celastrol Suppresses Growth and Induces Apoptosis of Human Hepatocellular Carcinoma through the Modulation of STAT3/JAK2 Signaling Cascade In Vitro and In Vivo
Celastrol Suppresses Growth and Induces Apoptosis of Human Hepatocellular Carcinoma through the Modulation of STAT3/JAK2 Signaling Cascade In Vitro and In Vivo
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DOI：
10.1158/1940-6207.capr-11-0420
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发表时间：
2012-04-01
影响因子：
3.3
通讯作者：
Sethi, Gautam
中科院分区：
文献类型：
--
作者：
Rajendran, Peramaiyan;Li, Feng;Sethi, Gautam
越来越多的证据表明，STAT3的组成性激活在肝细胞癌（HCC）的增殖、存活、转移和血管生成中起着关键作用，从而直接参与肝细胞癌（HCC）的发病机制。因此，能够抑制STAT3激活的新型药物具有预防和治疗hcc的潜力。研究了雷公藤红素对STAT3激活、相关蛋白激酶、STAT3调控基因产物、细胞增殖和凋亡的影响。研究了雷公藤红素对人肝癌异种移植瘤生长的体内影响。我们观察到，雷公藤红素抑制了组成型和诱导型STAT3的激活，这种抑制是通过抑制上游激酶c-Src以及janus活化激酶1和2的激活来介导的。钒酸盐治疗逆转了celastrol诱导的STAT3的调节，表明涉及酪氨酸磷酸酶。celastrol对STAT3激活的抑制导致了与增殖、存活和血管生成有关的各种基因产物的抑制。Celastrol还能抑制肝癌细胞的增殖并诱导细胞凋亡。最后，当腹腔注射时，雷公藤红素抑制肿瘤组织中STAT3的激活和人类HCC异种移植肿瘤在胸腺nu/nu小鼠中的生长，没有任何副作用。总之，我们的研究结果首次表明，在体外和体内，celastrol通过抑制肝癌细胞STAT3信号通路发挥其抗增殖和促凋亡作用。癌症预防；5 (4);631 - 43。(c) 2012年aacr。
Cumulative evidences(s) have established that the constitutive activation of STAT3 plays a pivotal role in the proliferation, survival, metastasis, and angiogenesis and thus can contribute directly to the pathogenesis of hepatocellular carcinoma (HCC). Thus, novel agents that can inhibit STAT3 activation have potential for both prevention and treatment of HCCs. The effect of celastrol on STAT3 activation, associated protein kinases, STAT3-regulated gene products, cellular proliferation, and apoptosis was investigated. The in vivo effect of celastrol on the growth of human HCC xenograft tumors in athymic nu/nu mice was also examined. We observed that celastrol inhibited both constitutive and inducible STAT3 activation, and the suppression was mediated through the inhibition of activation of upstream kinases c-Src, as well as Janus-activated kinase-1 and -2. Vanadate treatment reversed the celastrol-induced modulation of STAT3, suggesting the involvement of a tyrosine phosphatase. The inhibition of STAT3 activation by celastrol led to the suppression of various gene products involved in proliferation, survival, and angiogenesis. Celastrol also inhibited the proliferation and induced apoptosis in HCC cells. Finally, when administered intraperitoneally, celastrol inhibited STAT3 activation in tumor tissues and the growth of human HCC xenograft tumors in athymic nu/nu mice without any side effects. Overall, our results suggest for the first time that celastrol exerts its antiproliferative and proapoptotic effects through suppression of STAT3 signaling in HCC both in vitro and in vivo. Cancer Prev Res; 5(4); 631-43. (C) 2012 AACR.