Autophagy Inhibition by Sustained Overproduction of IL6 Contributes to Arsenic Carcinogenesis

作者：Qi, Yuanlin; Zhang, Mingfang; Li, Hui; Frank, Jacqueline A.; Dai, Lu; Liu, Huijuan; Zhang, Zhuo; Wang, Chi; Chen, Gang^*

来源：Cancer Research, 2014, 74(14): 3740-3752.

DOI：10.1158/0008-5472.CAN-13-3182

• BCL-2 FAMILY-MEMBERS
• BECLIN 1
• EPITHELIAL-CELLS
• COLORECTAL-CANCER
• LUNG-CANCER
• INFLAMMATION
• PATHWAY
• IL-6
• TRANSFORMATION
• APOPTOSIS

Chronic inflammation has been implicated as an etiologic factor in cancer, whereas autophagy may help preserve cancer cell survival but exert anti-inflammatory effects. How these phenomenas interact during carcinogenesis remains unclear. We explored this question in a human bronchial epithelial cell-based model of lung carcinogenesis that is mediated by subchronic exposure to arsenic. We found that sustained overexpression of the pro-inflammatory IL6 promoted arsenic-induced cell transformation by inhibiting autophagy. Conversely, strategies to enhance autophagy counteracted the effect of IL6 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 IL6 overexpression was sufficient to block autophagy by supporting Beclin-1/Mcl-1 interaction. Overall, our findings argued that chronic inflammatory states driven by IL6 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.

• 出版日期2014-7-15
• 单位福建医科大学