1. High-fat diet impairs ferroptosis and promotes cancer invasiveness via downregulating tumor suppressor ACSL4 in lung adenocarcinoma.
- Author
-
Zhang, Yixiang, Li, Songyu, Li, Fengzhou, Lv, Changsheng, and Yang, Qing-kai
- Subjects
- *
HIGH-fat diet , *CANCER invasiveness , *ADENOCARCINOMA , *LUNGS , *LABORATORY mice - Abstract
Background: Long-chain acyl-CoA synthetase-4 (ACSL4) is involved in fatty acid metabolism, and aberrant ACSL4 expression could be either tumorigenic or tumor-suppressive in different tumor types. However, the function and clinical significance of ACSL4 in lung adenocarcinoma remain elusive. Results: ACSL4 was frequently downregulated in lung adenocarcinoma when analyzing both the TCGA database and the validation samples, and the lower ACSL4 expression was correlated with a worse prognosis. Using gene set enrichment analysis, we found that high ACSL4 expression was frequently associated with the oxidative stress pathway, especially ferroptosis-related proteins. In vitro functional studies showed that knockdown of ACSL4 increased tumor survival/invasiveness and inhibited ferroptosis, while ACSL4 overexpression exhibited the opposite effects. Moreover, high-fat treatment could also inhibit erastin-induced ferroptosis by affecting ACSL4 expression. The anti-tumor effects of ferroptosis inducers and the anti-ferroptosis effects of the high-fat diet were further validated using the mouse xenograft model. Conclusions: ACSL4 plays a tumor-suppressive role in lung adenocarcinoma by suppressing tumor survival/invasiveness and promoting ferroptosis. Our study provided a theoretical reference for the application of ferroptotic inducers and dietary guidance for lung adenocarcinoma patients. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF