ACSL4 suppresses glioma cells proliferation via activating ferroptosis

Abstract

Acyl-CoA synthetase long-chain family member 4 (ACSL4) is a member of the long chain family of acyl-CoA synthetase proteins, which have recently been shown to serve an important role in ferroptosis. Previous studies have suggested that ferroptosis is involved in the occurrence of glioma; however, the role of ACSL4 in glioma remains unknown. In the present study, a reduction of ferroptosis in human glioma tissues and glioma cells was observed. Subsequently, it was demonstrated that the expression of ACSL4 was also downregulated in human glioma tissues and cells. A ferroptosis inhibitor and inducer were used to investigate the effects of ferroptosis on viability. The results showed that promoting ferroptosis inhibited the proliferation of glioma cells, and that the use of inducers had the reverse effect. Therefore, it was hypothesized that the reduction in ACSL4 expression may have been involved in ferroptosis and proliferation in glioma. Overexpression of ACSL4 decreased expression of glutathione peroxidase 4 and increased the levels of ferroptotic markers, including 5-hydroxyeicosatetraenoic (HETE), 12-HETE and 15-HETE. Additionally, ACSL4 overexpression resulted in an increase in lactate dehydrogenase release and a reduction in cell viability. The opposite results were observed when ACSL4 was silenced. These findings suggest that ACSL4 regulates ferroptosis and proliferation of glioma cells. To further investigate the mechanism underlying ACSL4-mediated regulation of proliferation in glioma cells, cells were treated with small interfering (si)-ACSL4 and sorafenib, a ferroptosis inducer. sorafenib attenuated the ability of siRNA-mediated silencing of ACSL4, thus improving cell viability. These results demonstrate that ACSL4 protects glioma cells and exerts anti-proliferative effects by activating a ferroptosis pathway and highlight the pivotal role of ferroptosis regulation by ACSL4 in its protective effects on glioma. Therefore, ACSL4 may serve as a novel therapeutic target for the treatment of glioma.

A Potential Mechanism of Temozolomide Resistance in Glioma–Ferroptosis

“…The siRNA-mediated silencing of ACSL4 promoted the proliferation in glioma cells via the decrease in ferroptosis through the enhancement of GPX4 expression. All these results suggest that ACSL4 inhibition directly affects the expression of GPx4, which finally promotes glioma cell proliferation by inhibiting ferroptosis (68). As mentioned above, GPX4 plays an important role in the resistance of tumor cells by regulating ferroptosis.…”

Identification of ACSL4 as a biomarker and contributor of ferroptosis in clear cell renal cell carcinoma

“…In addition to the crosstalk between ferroptosis and other forms of cell death, the function and assay of ferroptosis related molecular and pathway need to be investigated. Some newly reported proteins such as PEBP1 [15], NCOA4 [16], and metallothionein-1G [17] are correlated with ferroptosis via iron metabolism and lipid peroxidation. In our GO and KEGG analysis, we found that the gene co-expressed with ACSL4 is enriched in the pathway of protein ubiquitination.…”

Crosstalk Between Autophagy and Ferroptosis and Its Putative Role in Ischemic Stroke

“…During this step, peroxidation of polyunsaturated fatty acids (PUFAs) has been considered as a key player ( Kagan et al, 2017 ). Two enzymes, acyl-CoA synthetase long chain family member 4 (ACSL4) and lysophosphatidylcholine Acyltransferase 3 (LPCAT3), have been identified to be responsible for the biosynthesis and remodeling of PUFA-containing phospholipid, while inhibiting ACSL4 or LPCAT3 prevents ferroptotic cell death ( Yuan et al, 2016 ; Li et al, 2019 ; Cheng et al, 2020 ). Then, oxidation of PUFA-phosphatidylethanolamines by cyclooxygenases, lipoxygenases (LOX) and cytochromes P450 lead to the accumulation of peroxides, finally contributing to the generation of lipid peroxides ( Yang et al, 2016 ; Çolakoğlu et al, 2018 ; Tyurina et al, 2018 ).…”