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. ©2014 AACR.
CITATION STYLE
Qi, Y., Zhang, M., Li, H., Frank, J. A., Dai, L., Liu, H., … Chen, G. (2014). Autophagy inhibition by sustained overproduction of IL6 contributes to arsenic carcinogenesis. Cancer Research, 74(14), 3740–3752. https://doi.org/10.1158/0008-5472.CAN-13-3182
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