期刊
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
卷 478, 期 3, 页码 1338-1343出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2016.08.124
关键词
ACSL; Ferroptosis; Lipid metabolism; Biomarker; Hydroxyeicosatetraenoic acid
资金
- US National Institutes of Health [R01GM115366, R01CA160417]
- Natural Science Foundation of Guangdong Province [2016A030308011]
- Natural Science Foundation of Jilin Province [20160519001JH]
- Innovation Team of Education Department of Jilin Province [2016020]
- Norman Bethune Program of Jilin University [2015334]
- American Cancer Society Research Scholar Grant [RSG-16-014-01-CDD]
Ferroptosis, a recently identified form of non- apoptotic cell death, is involved in several physiological and pathological rocesses. Although lipid peroxidation plays a central role in triggering ferroptosis, the essential regulator of lipid metabolism in ferroptosis remains poorly defined. Here, we show that acylCoA synthetase long- chain family member 4 ( ACSL4) is required for ferroptotic cancer cell death. Compared with ferroptosis- sensitive cells (e.g., HepG2 and HL60), the expression of ACSL4 was remarkably downregulated in ferroptosis- resistant cells (e.g., LNCaP and K562). In contrast, the expression of other ACSLs, including ACSL1, ACSL3, ACSL5, and ACSL6, did not correlate with ferroptosis sensitivity. Moreover, knockdown of ACSL4 by specific shRNA inhibited erastin- induced ferroptosis in HepG2 and HL60 cells, whereas overexpression of ACSL4 by gene transfection restored sensitivity of LNCaP and K562 cells to erastin. Mechanically, ACSL4-mediated production of 5-hydroxyeicosatetraenoic acid (5-HETE) contributed to ferroptosis. Pharmacological inhibition of 5-HETE production by zileuton limited ACSL4 overexpression-induced ferroptosis. Collectively, these results indicate that ACSL4 is not only a sensitive monitor of ferroptosis, but also an important contributor of ferroptosis. (c) 2016 Elsevier Inc. All rights reserved.
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