Acid-induced autophagy protects human lung cancer cells from apoptosis by activating ER stress

作者：Xie, Wen-Yue; Zhou, Xiang-Dong^*; Li, Qi; Chen, Ling-Xiu; Ran, Dan-Hua

来源：Experimental Cell Research, 2015, 339(2): 270-279.

DOI：10.1016/j.yexcr.2015.11.005

• Tumor microenvironment
• Acid
• Autophagy
• Lung cancer
• ER stress
• Apoptosis

An acidic tumor microenvironment exists widely in solid tumors. However, the detailed mechanism of cell survival under acidic stress remains unclear. The aim of this study is to clarify whether acid-induced autophagy exists and to determine the function and mechanism of autophagy in lung cancer cells. We have found that acute low pH stimulated autophagy by increasing LC3-positive punctate vesicles, increasing LC3 II expression levels and reducing p62 protein levels. Additionally, autophagy was inhibited by the addition of Baf or knockdown of Beclin 1, and cell apoptosis was increased markedly. In mouse tumors, the expression of cleaved caspase3 and p62 was enhanced by oral treatment with sodium bicarbonate, which can raise the intratumoral pH. Furthermore, the protein levels of ER stress markers, including p-PERK, p-eIF2 alpha, CHOP, XBP-1s and GRP78, were also increased in response to acidic pH. The antioxidant NAC, which reduces ROS accumulation, alleviated acid-mediated ER stress and autophagy, and knocking down GRP78 reduced autophagy activation under acidic conditions, which suggests that autophagy was induced by acidic pH through ER stress. Taken together, these results indicate that the acidic microenvironment in non-small cell lung cancer cells promotes autophagy by increasing ROS-ER stress, which serves as a survival adaption in this setting.

• 出版日期2015-12-10
• 单位重庆医科大学