Autophagy inhibition by sustained overproduction of IL6 contributes to arsenic carcinogenesis.
Autophagy inhibition by sustained overproduction of IL6 contributes to arsenic carcinogenesis.
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DOI：
10.1158/0008-5472.can-13-3182
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发表时间：
2014-07-15
期刊：
影响因子：
11.2
通讯作者：
Chen G
中科院分区：
文献类型：
--
作者：
Qi Y;Zhang M;Li H;Frank JA;Dai L;Liu H;Zhang Z;Wang C;Chen G
慢性炎症被认为是癌症的一个病因，而自噬可能有助于保持癌细胞存活，但具有抗炎作用。这些现象在癌变过程中如何相互作用仍不清楚。我们在亚慢性砷暴露介导的人支气管上皮细胞肺癌模型中探讨了这个问题。我们发现促炎白细胞介素IL-6的持续过度表达通过抑制自噬促进砷诱导的细胞转化。相反，增强自噬的策略抵消了IL-6在模型中的作用。这些发现在砷诱导的肺癌小鼠模型中得到了证实和扩展。机制研究表明，mTOR抑制有助于自噬的激活，而IL-6过表达足以通过支持Beclin-1/Mcl-1相互作用来阻止自噬。总的来说，我们的研究结果表明，由IL-6驱动的慢性炎症状态可以拮抗自噬状态，这可能有助于保持癌细胞存活并促进恶性进展，这表明需要将炎症和自噬控制分离以使肿瘤进展。
Chronic inflammation has been implicated as an etiological factor in cancer, whereas autophagy may help preserve cancer cell survival but exert anti-inflammatory effects. How these phenomena interact during carcinogenesis remains unclear. We explored this question in a human bronchial epithelial cell-based model of lung carcinogenesis that is mediated by sub-chronic exposure to arsenic. We found that sustained overexpression of the pro-inflammatory interleukin IL-6 promoted arsenic-induced cell transformation by inhibiting autophagy. Conversely, strategies to enhance autophagy counteracted the effect of IL-6 in the model. These findings were confirmed and extended in a mouse model of arsenic-induced lung cancer. Mechanistic investigations suggested that mTOR inhibition contributed to the activation of autophagy, whereas IL-6 overexpression was sufficient to block autophagy by supporting Beclin-1/Mcl-1 interaction. Overall, our findings argued that chronic inflammatory states driven by IL-6 could antagonize autophagic states that may help preserve cancer cell survival and promote malignant progression, suggesting a need to uncouple inflammation and autophagy controls to enable tumor progression.