Acquired cisplatin resistance in human ovarian A2780 cancer cells correlates with shift in taurine homeostasis and ability to volume regulate
Acquired cisplatin resistance in human ovarian A2780 cancer cells correlates with shift in taurine homeostasis and ability to volume regulate
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DOI：
10.1152/ajpcell.00274.2014
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发表时间：
2014-12-15
影响因子：
5.5
通讯作者：
Lambert, Ian Henry
中科院分区：
文献类型：
--
作者：
Sorensen, Belinda Halling;Thorsteinsdottir, Unnur Arna;Lambert, Ian Henry
顺铂耐药是癌症治疗中的一个主要挑战，它是通过减少药物积累和增强避免药物诱导的细胞损伤、细胞收缩和细胞凋亡的能力而发展起来的。半必需氨基酸牛磺酸的摄取和释放有助于细胞体积稳态，牛磺酸已被报道具有抗凋亡作用。在这里，我们发现在顺铂敏感的[野生型（WT）]人卵巢癌A2780细胞中，在磷脂酶A(2)抑制剂溴烯醇内酯、5-脂氧合酶（5-LO）抑制剂ETH 615-139和半胱氨酸白三烯受体1 （CysLT1）拮抗剂zafirlukast的存在下，体积敏感的牛磺酸释放减少，并被阴离子通道阻滞剂DIDS（4,4'-二异硫氰酸二苯乙烯-2,2'-二磺酸盐）破坏。比较WT和顺铂耐药（RES） A2780细胞，我们还发现，在RES A2780细胞中，逃避顺铂诱导的细胞死亡与牛磺酸积累增加相关，这是由于牛磺酸摄取增加和伴随的体积敏感的牛磺酸释放途径受损，以及渗透性细胞肿胀后无法减少细胞体积。RES A2780细胞中体积敏感牛磺酸释放的下调与富含亮氨酸的重复序列蛋白8A （LRRC8A）的表达减少相关。此外，急性（18小时）暴露于顺铂（5-10 μ M）会增加WT A2780细胞中牛磺酸的释放和LRRC8A的表达，而顺铂对RES A2780细胞中LRRC8A的表达没有影响。提示LRRC8A活性的变化可作为细胞凋亡进程和耐药获得的生物标志物。
Cisplatin resistance is a major challenge in the treatment of cancer and develops through reduced drug accumulation and an increased ability to avoid drug-induced cell damage, cell shrinkage, and hence initiation of apoptosis. Uptake and release of the semiessential amino acid taurine contribute to cell volume homeostasis, and taurine has been reported to have antiapoptotic effects. Here we find that volume-sensitive taurine release in cisplatin-sensitive [wild-type (WT)] human ovarian cancer A2780 cells is reduced in the presence of the phospholipase A(2) inhibitor bromenol lactone, the 5-lipoxygenase (5-LO) inhibitor ETH 615-139, and the cysteine leukotriene receptor 1 (CysLT1) antagonist zafirlukast and impaired by the anion channel blocker DIDS (4,4'-diisothiocyanatostilbene-2,2'-disulfonate). Comparing WT and cisplatin-resistant (RES) A2780 cells we also find that evasion of cisplatin-induced cell death in RES A2780 cells correlates with an increased accumulation of taurine, due to an increased taurine uptake and a concomitant impairment of the volume-sensitive taurine release pathway, as well an inability to reduce cell volume after osmotic cell swelling. Downregulation of volume-sensitive taurine release in RES A2780 cells correlates with reduced expression of the leucine-rich repeat-containing protein 8A (LRRC8A). Furthermore, acute (18 h) exposure to cisplatin (5-10 mu M) increases taurine release and LRRC8A expression in WT A2780 cells whereas cisplatin has no effect on LRRC8A expression in RES A2780 cells. It is suggested that shift in LRRC8A activity can be used as biomarker for apoptotic progress and acquirement of drug resistance.