STAT5A-mediated SOCS2 expression regulates Jak2 and STAT3 activity following c-Src inhibition in head and neck squamous carcinoma.
STAT5A-mediated SOCS2 expression regulates Jak2 and STAT3 activity following c-Src inhibition in head and neck squamous carcinoma.
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DOI：
10.1158/1078-0432.ccr-11-1889
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发表时间：
2012-01-01
期刊：
影响因子：
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通讯作者：
Johnson FM
中科院分区：
文献类型：
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作者：
Sen B;Peng S;Woods DM;Wistuba I;Bell D;El-Naggar AK;Lai SY;Johnson FM
c-Src的抑制导致癌细胞侵袭的显著减少，但对细胞存活的影响是适度的。定义c-Src抑制后限制细胞凋亡的机制可能会导致一种理想的治疗方法，既抑制侵袭，又导致细胞凋亡。在这方面，我们发现了一个新的反馈回路，导致STAT 3重新激活后持续的c-Src抑制。在这里，我们定义了这个反馈回路的机制，并检查在体内抑制它的效果。我们测量的水平和活动的途径组件使用PCR，蛋白质印迹法，和激酶测定后，他们的操纵使用分子和药理学方法。我们利用了一种异种移植动物模型，其中人口腔鳞状细胞癌仅在体内维持。c-Src抑制后，STAT 5被持久抑制。STAT 5A的抑制，而不是STAT 5 B的抑制，随后降低细胞因子信号传导抑制因子2（SOCS 2）的表达。SOCS 2抑制Janus激酶2（Jak 2）活性和Jak 2-STAT 3结合。SOCS 2表达对于c-Src抑制剂抑制STAT 3是必需的。SOCS 2的过表达足以防止STAT 3再激活并增强c-Src抑制的细胞毒性作用。同样地，Jak和c-Src抑制剂的组合导致比单独的任一药剂在体内显著更多的细胞凋亡。据我们所知，我们的研究是第一个完全定义这种反馈回路机制的研究，其中持续的c-Src抑制通过持续抑制STAT 5A导致SOCS 2表达减少，从而激活Jak 2和STAT 3，Jak 2-STAT 3结合和生存信号。
The inhibition of c-Src results in a striking reduction in cancer cell invasion, but the effect on cell survival is modest. Defining mechanisms that limit apoptosis following c-Src inhibition could result in an ideal therapeutic approach that both inhibits invasion and leads to apoptosis. In this regard, we discovered a novel feedback loop that results in STAT3 reactivation following sustained c-Src inhibition. Here we define the mechanism underlying this feedback loop and examine the effect of inhibiting it in vivo. We measured levels and activity of pathway components using PCR, Western blotting, and kinase assays following their manipulation using both molecular and pharmacologic approaches. We utilized a heterotransplant animal model in which human oral squamous cancer is maintained exclusively in vivo. Following c-Src inhibition, STAT5 is durably inhibited. The inhibition of STAT5A, but not STAT5B, subsequently reduces the expression of suppressors of cytokine signaling 2 (SOCS2). SOCS2 inhibits Janus kinase 2 (Jak2) activity and Jak2-STAT3 binding. SOCS2 expression is necessary for STAT3 inhibition by c-Src inhibitors. Overexpression of SOCS2 is adequate to prevent STAT3 reactivation and to enhance the cytotoxic effects of c-Src inhibition. Likewise, the combination of Jak and c-Src inhibitors led to significantly more apoptosis than either agent alone in vivo. To our knowledge, ours is the first study that fully defines the mechanism underlying this feedback loop, in which sustained c-Src inhibition leads to diminished SOCS2 expression via sustained inhibition of STAT5A, allowing activation of Jak2 and STAT3, Jak2-STAT3 binding, and survival signals.