Overexpression of Bcl-2 induces STAT-3 activation via an increase in mitochondrial superoxide.
Overexpression of Bcl-2 induces STAT-3 activation via an increase in mitochondrial superoxide.
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DOI：
10.18632/oncotarget.5763
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发表时间：
2015-10-27
期刊：
影响因子：
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通讯作者：
Pervaiz S
中科院分区：
文献类型：
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作者：
Kang J;Chong SJ;Ooi VZ;Vali S;Kumar A;Kapoor S;Abbasi T;Hirpara JL;Loh T;Goh BC;Pervaiz S
我们最近报道了一种新的Bcl2和rac1之间的相互作用，并将其与Bcl2在癌细胞中诱导促氧化状态的能力联系在一起。为了进一步了解这种相互作用的功能相关性，我们利用计算机模拟，基于Cellworks Group Inc.创建的蛋白质途径动态网络。在与rac1和/或Bcl-2表达水平正相关的靶标中确定了STAT3。证实了这一点，p-Tyr705标记的STAT3的激活水平，特别是在线粒体中，在Bcl2过度表达的癌细胞中显著更高。Bcl2诱导的STAT3激活是GTP负载的RAC1和NADPH氧化酶(NOx)依赖的细胞内超氧化物歧化(O2·−)增加的函数。此外，BH-3特异性的BH-2抑制剂ABT199和沉默的Bcl-2也阻断了STAT3的磷酸化。有趣的是，在抑制细胞内O2·−阻断STAT3磷酸化的同时，野生型STAT3的瞬时过表达导致线粒体O2·−产量显著增加，这可被STAT3(Y705F)的功能突变体拯救。值得注意的是，在不同亚型的B细胞淋巴瘤患者的原发组织中，STAT3和/或Bcl2的表达和/或磷酸化之间存在很强的相关性。这些数据表明，在促进细胞存活的允许的氧化还原环境中，Bcl2、rac1和激活的STAT3之间存在功能上的串扰。结果还强调了涉及Bcl-2过表达、rac1激活和STAT3磷酸化的信号在根据疾病严重程度和化疗耐药对临床淋巴瘤进行分层的潜在实用价值。
We recently reported a novel interaction between Bcl-2 and Rac1 and linked that to the ability of Bcl-2 to induce a pro-oxidant state in cancer cells. To gain further insight into the functional relevance of this interaction, we utilized computer simulation based on the protein pathway dynamic network created by Cellworks Group Inc. STAT3 was identified among targets that positively correlated with Rac1 and/or Bcl-2 expression levels. Validating this, the activation level of STAT3, as marked by p-Tyr705, particularly in the mitochondria, was significantly higher in Bcl-2-overexpressing cancer cells. Bcl-2-induced STAT3 activation was a function of GTP-loaded Rac1 and NADPH oxidase (Nox)-dependent increase in intracellular superoxide (O2•−). Furthermore, ABT199, a BH-3 specific inhibitor of Bcl-2, as well as silencing of Bcl-2 blocked STAT3 phosphorylation. Interestingly, while inhibiting intracellular O2•− blocked STAT3 phosphorylation, transient overexpression of wild type STAT3 resulted in a significant increase in mitochondrial O2•− production, which was rescued by the functional mutants of STAT3 (Y705F). Notably, a strong correlation between the expression and/or phosphorylation of STAT3 and Bcl-2 was observed in primary tissues derived from patients with different sub-sets of B cell lymphoma. These data demonstrate the presence of a functional crosstalk between Bcl-2, Rac1 and activated STAT3 in promoting a permissive redox milieu for cell survival. Results also highlight the potential utility of a signature involving Bcl-2 overexpression, Rac1 activation and STAT3 phosphorylation for stratifying clinical lymphomas based on disease severity and chemoresistance.