ACSL4 suppresses glioma cells proliferation via activating ferroptosis
ACSL4 suppresses glioma cells proliferation via activating ferroptosis
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DOI：
10.3892/or.2019.7419
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发表时间：
2020-01-01
期刊：
影响因子：
4.2
通讯作者：
Chen, Qian-Xue
中科院分区：
文献类型：
--
作者：
Cheng, Jing;Fan, Yan-Qin;Chen, Qian-Xue
酰基辅酶A合成酶长链家族成员4（ACSL 4）是酰基辅酶A合成酶蛋白的长链家族的成员，其最近被证明在铁凋亡中起重要作用。以往的研究表明，铁凋亡参与胶质瘤的发生，但ACSL 4在胶质瘤中的作用仍然未知。在本研究中，观察到人胶质瘤组织和胶质瘤细胞中的铁凋亡减少。随后，证实ACSL 4在人脑胶质瘤组织和细胞中的表达也下调。使用铁凋亡抑制剂和诱导剂来研究铁凋亡对存活率的影响。结果表明，促进铁凋亡抑制胶质瘤细胞的增殖，而使用诱导剂则有相反的作用。因此，假设ACSL 4表达的减少可能参与了胶质瘤中的铁凋亡和增殖。ACSL 4的过表达降低了谷胱甘肽过氧化物酶4的表达，并增加了包括5-羟基二十碳四烯酸（HETE）、12-HETE和15-HETE在内的铁蛋白标记物的水平。此外，ACSL 4过表达导致乳酸脱氢酶释放增加和细胞活力降低。当ACSL 4沉默时，观察到相反的结果。这些发现表明ACSL 4调节胶质瘤细胞的铁凋亡和增殖。为了进一步研究ACSL 4介导的神经胶质瘤细胞增殖调节的机制，用小干扰（si）-ACSL 4和索拉非尼（一种铁凋亡诱导剂）处理细胞。索拉非尼减弱了siRNA介导的ACSL 4沉默的能力，从而提高了细胞活力。这些结果表明，ACSL 4保护胶质瘤细胞，并通过激活铁凋亡途径发挥抗增殖作用，并强调了ACSL 4在其对胶质瘤的保护作用中对铁凋亡的调节作用。因此，ACSL 4可能成为胶质瘤治疗的新靶点。
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.