CISD2 inhibition overcomes resistance to sulfasalazine-induced ferroptotic cell death in head and neck cancer
CISD2 inhibition overcomes resistance to sulfasalazine-induced ferroptotic cell death in head and neck cancer
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DOI：
10.1016/j.canlet.2018.06.018
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发表时间：
2018-01-01
期刊：
影响因子：
9.7
通讯作者：
Roh, Jong-Lyel
中科院分区：
文献类型：
--
作者：
Kim, Eun Hye;Shin, Daiha;Roh, Jong-Lyel
磺胺氮嗪已被重新用于通过抑制x(c)(-)-胱氨酸/谷氨酸反转运蛋白（xCT）诱导铁细胞死亡。然而，癌细胞能够发展出逃避细胞死亡的机制。因此，我们试图确定头颈癌（HNC）对磺胺吡啶诱导的铁下垂耐药的分子机制。在不同HNC细胞株上观察了磺胺氮嗪和吡格列酮的作用。通过评估细胞活力、细胞死亡、脂质ROS生成、线粒体铁和小鼠肿瘤异种移植模型来确定这些药物的作用以及CISD2基因的抑制和过表达。SAS诱导HNC不同程度的铁致细胞死亡。CISD2的表达与铁下垂抗性之间存在相关性。CISD2过表达赋予了柳氮磺胺嘧啶对铁下垂的抗性。沉默CISD2基因使耐药HNC细胞易受磺胺嘧啶诱导的铁下垂，脂质ROS和线粒体铁铁水平升高。在体外和小鼠肿瘤异种移植模型中，吡格列酮诱导线粒体铁和ROS的过度积累，并使耐药的HNC细胞对磺胺氮嗪敏感。通过增加线粒体铁铁和脂质ROS的积累，CISD2抑制克服了HNC对磺胺氮嗪诱导的铁细胞死亡的抗性。
Sulfasalazine has been repurposed to induce ferroptotic cancer cell death via inhibition of x(c)(-)-cystine/glutamate antiporter (xCT). However, cancer cells are capable of developing mechanisms to evade cell death. Therefore, we sought to determine the molecular mechanisms underlying resistance to sulfasalazine-induced ferroptosis in head and neck cancer (HNC). The effects of sulfasalazine and pioglitazone were tested in various HNC cell lines. The effects of these drugs and inhibition and overexpression of CISD2 gene were determined by evaluating viability, cell death, lipid ROS production, mitochondria] iron, and mouse tumor xenograft models. SAS induced ferroptotic cell death in HNC at different levels. CISD2 expression showed an association between its expression and ferroptosis resistance. CISD2 overexpression conferred resistance to ferroptosis by sulfasalazine. Silencing CISD2 gene rendered resistant HNC cells susceptible to sulfasalazine-induced ferroptosis, with increased levels of lipid ROS and mitochondrial ferrous iron. Pioglitazone induced over-accumulation of mitochondria] iron and ROS and sensitized resistant HNC cells to sulfasalazine treatment in Vitro and in a mouse tumor-xenograft model. CISD2 inhibition overcomes HNC resistance to ferroptotic cell death induced by sulfasalazine via increased accumulation of mitochondrial ferrous iron and lipid ROS.