Luteolin selectively kills STAT3 highly activated gastric cancer cells through enhancing the binding of STAT3 to SHP-1.
Luteolin selectively kills STAT3 highly activated gastric cancer cells through enhancing the binding of STAT3 to SHP-1.
复制标题
木犀草素通过增强STAT3与SHP-1的结合选择性杀死STAT3高度激活的胃癌细胞
DOI：
10.1038/cddis.2017.38
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发表时间：
2017-02-09
影响因子：
9
通讯作者：
Gao Q
中科院分区：
文献类型：
--
作者：
Song S;Su Z;Xu H;Niu M;Chen X;Min H;Zhang B;Sun G;Xie S;Wang H;Gao Q
植物类黄酮木犀草素在胃癌细胞中的抗肿瘤作用尚不完全清楚。在这里，我们表明木犀草素选择性地杀死STAT3过度激活的GC细胞，这些细胞通常具有耐药性。木犀草素在这些GC细胞中的处理显著抑制STAT3磷酸化，降低STAT3靶向基因Mcl-1、Survivin和Bcl-xl的表达。沉默蛋白酪氨酸磷酸酶SHP-1可消除木犀草素对STAT3和细胞凋亡的抑制作用，提示SHP-1在木犀草素介导的细胞功能中起关键作用。此外，SHP-1对STAT3去磷酸化的木犀草素作用涉及到HSP-90，通过形成HSP-90/STAT3复合物来保护STAT3磷酸化。因此，木犀草素通过破坏HSP-90与STAT3的结合抑制STAT3的激活，从而促进其与SHP-1的相互作用，导致STAT3的去磷酸化。小鼠GC细胞异种移植模型证实了木犀草素在体内抑制肿瘤生长的有效性。
The antitumor effect of luteolin, a plant flavonoid, in gastric cancer (GC) cells has not been fully understood. Here we show that luteolin selectively kills STAT3 overactivated GC cells that are often drug resistant. The treatment of luteolin in these GC cells significantly inhibited STAT3 phosphorylation and reduced the expression of STAT3 targeting gene Mcl-1, Survivin and Bcl-xl. Silencing of SHP-1, a protein tyrosine phosphatase, abolished the inhibitory effect of luteolin on STAT3 and cell apoptosis, suggesting that SHP-1 is crucial in luteolin-mediated cellular function. Moreover, this luteolin effect of STAT3 dephosphorylation by SHP-1 involved in HSP-90, which protected STAT3 phosphorylation by forming HSP-90/STAT3 complex. Thus, luteolin inhibited STAT3 activation through disrupting the binding of HSP-90 to STAT3, which promoted its interaction to SHP-1, resulted in the dephosphorylation of STAT3. The GC cell xenograft mouse model confirmed the effectiveness of luteolin induced inhibition of tumor growth in vivo.