Chromium (Cr) (VI) compounds are known to be serious toxic and carcinogenic, but the mechanism is not clear. In our previous study, we found that Cr (VI)-induced ER stress plays an important role in the crosstalk between apoptosis and autophagy, while autophagy was apoptosis-dependent and subsequently prevents apoptosis cell death to keep A549 cells resistant to Cr (VI)-induced toxicity. In this study, we found that Cr (VI) could induce aerobic glycolysis in A549 cells. Both ER stress inhibitor, phenylbutyric acid (4-PBA) and the inhibitor of autophagy, 3-MA, repressed Cr (VI)-induced glycolysis, indicating that both ER stress and autophagy were involved in Cr (VI)-induced glycolysis in A549 cells. Co-treatment of the inhibitor of aerobic glycolysis, 2-DG and Cr (VI) for 24 h increased Cr (VI)-induced cleaved caspase-3, caspase-9 and the number of apoptotic cells, demonstrating that aerobic glycolysis played an important role in attenuating Cr (VI)-induced apoptosis. Furthermore, knockdown of ATF4 by siATF4 significantly decreased Cr (VI)-induced aerobic glycolysis and apoptosis, suggesting that ATF4 was involved in Cr (VI)-induced aerobic glycolysis and its effect of attenuating apoptosis in A549 cells. Taken together, our results demonstrated that autophagy-dependent glycolysis played a role in attenuating Cr (VI)-induced apoptosis. ER stress was involved in facilitating glycolysis, whose induction was mediated by ATF4. These findings open a window for the development of therapeutic interventions to prevent Cr (VI)-induced toxicity.

中文翻译：

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ATF4介导的自噬依赖性糖酵解在减弱Cr（VI）诱导的A549细胞凋亡中起重要作用

已知铬 (Cr) (VI) 化合物具有严重的毒性和致癌性，但其机制尚不清楚。在我们之前的研究中，我们发现 Cr (VI) 诱导的 ER 应激在细胞凋亡和自噬之间的串扰中起重要作用，而自噬是凋亡依赖性的，随后阻止细胞凋亡细胞死亡以保持 A549 细胞对 Cr (VI) 的抗性-诱导毒性。在这项研究中，我们发现 Cr (VI) 可以诱导 A549 细胞中的有氧糖酵解。ER应激抑制剂苯基丁酸（4-PBA）和自噬抑制剂3-MA均抑制Cr（VI）诱导的糖酵解，表明ER应激和自噬都参与了A549中Cr（VI）诱导的糖酵解细胞。有氧糖酵解抑制剂 2-DG 和 Cr (VI) 共同处理 24 小时会增加 Cr (VI) 诱导的裂解 caspase-3，caspase-9 和凋亡细胞的数量，表明有氧糖酵解在减弱 Cr (VI) 诱导的细胞凋亡中起重要作用。此外，siATF4 对 ATF4 的敲低显着降低了 Cr (VI) 诱导的有氧糖酵解和细胞凋亡，表明 ATF4 参与了 Cr (VI) 诱导的有氧糖酵解及其减弱 A549 细胞凋亡的作用。总之，我们的结果表明自噬依赖性糖酵解在减弱 Cr (VI) 诱导的细胞凋亡中起作用。内质网应激参与促进糖酵解，其诱导由 ATF4 介导。这些发现为开发治疗干预措施以预防 Cr (VI) 诱导的毒性打开了一扇窗。此外，siATF4 对 ATF4 的敲低显着降低了 Cr (VI) 诱导的有氧糖酵解和细胞凋亡，表明 ATF4 参与了 Cr (VI) 诱导的有氧糖酵解及其减弱 A549 细胞凋亡的作用。总之，我们的结果表明自噬依赖性糖酵解在减弱 Cr (VI) 诱导的细胞凋亡中起作用。内质网应激参与促进糖酵解，其诱导由 ATF4 介导。这些发现为开发治疗干预措施以预防 Cr (VI) 诱导的毒性打开了一扇窗。此外，siATF4 对 ATF4 的敲低显着降低了 Cr (VI) 诱导的有氧糖酵解和细胞凋亡，表明 ATF4 参与了 Cr (VI) 诱导的有氧糖酵解及其减弱 A549 细胞凋亡的作用。总之，我们的结果表明自噬依赖性糖酵解在减弱 Cr (VI) 诱导的细胞凋亡中起作用。内质网应激参与促进糖酵解，其诱导由 ATF4 介导。这些发现为开发治疗干预措施以预防 Cr (VI) 诱导的毒性打开了一扇窗。我们的结果表明，自噬依赖性糖酵解在减弱 Cr (VI) 诱导的细胞凋亡中起作用。内质网应激参与促进糖酵解，其诱导由 ATF4 介导。这些发现为开发治疗干预措施以预防 Cr (VI) 诱导的毒性打开了一扇窗。我们的结果表明，自噬依赖性糖酵解在减弱 Cr (VI) 诱导的细胞凋亡中起作用。内质网应激参与促进糖酵解，其诱导由 ATF4 介导。这些发现为开发治疗干预措施以预防 Cr (VI) 诱导的毒性打开了一扇窗。