Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.
Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.
Oncol Rep. 2020 Jan;43(1):147-158. doi: 10.3892/or.2019.7419. Epub 2019 Nov 27.
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.
酰基辅酶 A 合成酶长链家族成员 4（ACSL4）是酰基辅酶 A 合成酶蛋白长链家族的成员，最近研究表明其在铁死亡中发挥重要作用。先前的研究表明，铁死亡与脑胶质瘤的发生有关；然而，ACSL4 在脑胶质瘤中的作用尚不清楚。在本研究中，观察到人胶质瘤组织和胶质瘤细胞中的铁死亡减少。随后，证明 ACSL4 的表达也在人胶质瘤组织和细胞中下调。使用铁死亡抑制剂和诱导剂来研究铁死亡对细胞活力的影响。结果表明，促进铁死亡抑制了胶质瘤细胞的增殖，而诱导剂的使用则产生了相反的效果。因此，假设 ACSL4 表达的减少可能与脑胶质瘤中的铁死亡和增殖有关。ACSL4 的过表达降低了谷胱甘肽过氧化物酶 4 的表达并增加了铁死亡标志物的水平，包括 5-羟基二十碳四烯酸（HETE）、12-HETE 和 15-HETE。此外，ACSL4 过表达导致乳酸脱氢酶释放增加和细胞活力降低。当 ACSL4 被沉默时，观察到相反的结果。这些发现表明 ACSL4 调节脑胶质瘤细胞的铁死亡和增殖。为了进一步研究 ACSL4 介导的脑胶质瘤细胞增殖调控的机制，用小干扰（si）-ACSL4 和索拉非尼（一种铁死亡诱导剂）处理细胞。索拉非尼减弱了 siRNA 介导的 ACSL4 沉默的能力，从而提高了细胞活力。这些结果表明，ACSL4 通过激活铁死亡途径来保护胶质瘤细胞并发挥抗增殖作用，并强调了 ACSL4 对铁死亡的调节在其对胶质瘤的保护作用中的关键作用。因此，ACSL4 可能成为治疗脑胶质瘤的新治疗靶点。
