High-fat diet impairs ferroptosis and promotes cancer invasiveness via downregulating tumor suppressor ACSL4 in lung adenocarcinoma

Biology Direct

Songyu Li¹  Qing-kai Yang¹  Changsheng Lv²  Yixiang Zhang²  Fengzhou Li² 

[1] Department of Oncology, Institute of Cancer Stem Cell, Dalian Medical University, 9 Western Lvshun South Road, 116044, Dalian, Liaoning, China;Department of Thoracic Surgery, The First Affiliated Hospital of Dalian Medicine University, No. 222 Zhongshan Road, 116000, Dalian, Liaoning, China;

关键词: Long-chain acyl-CoA synthetase-4;    Ferroptosis;    Lung adenocarcinoma;    High-fat diet;   

DOI  :  10.1186/s13062-021-00294-7

来源: Springer

【 摘 要 】

BackgroundLong-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.ResultsACSL4 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.ConclusionsACSL4 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.

【 授权许可】

CC BY