Expression of Ferredoxin1 in cisplatin-resistant ovarian cancer cells confers their resistance against ferroptosis induced by cisplatin
Expression of Ferredoxin1 in cisplatin-resistant ovarian cancer cells confers their resistance against ferroptosis induced by cisplatin
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DOI：
10.3892/or.2023.8561
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发表时间：
2023-06-01
期刊：
影响因子：
4.2
通讯作者：
Minami, Yasuhiro
中科院分区：
文献类型：
--
作者：
Takahashi, Ryosuke;Kamizaki, Koki;Minami, Yasuhiro
卵巢癌（OC）是一种难治性癌症，由于对抗癌药物（包括顺铂）产生耐药性而显示复发。然而，肿瘤细胞获得顺铂耐药性的分子机制在很大程度上仍然未知。在本研究中，使用了两组卵巢癌细胞系：亲本A2780细胞系、OVK 18细胞系及其衍生的顺铂耐药细胞。结果发现，顺铂可以诱导铁凋亡在这些亲本细胞通过增强线粒体膜电位和脂质过氧化，通过流式细胞仪分析评估，铁氧还蛋白1（Fdx 1），定位于线粒体的铁硫蛋白的表达，可以上调顺铂耐药细胞在顺铂的情况下。有趣的是，研究表明，siRNA介导的顺铂耐药细胞中Fdx 1的耗竭通过增加顺铂诱导的线粒体膜电位和脂质过氧化而导致铁凋亡增强。免疫组化法检测卵巢癌患者临床标本中Fdx 1的表达，发现顺铂耐药标本中Fdx 1的表达高于顺铂敏感标本。总之，这些结果表明，Fdx 1可能是一种新的和合适的诊断/预后标记物和治疗顺铂耐药OC的分子靶点。
Ovarian cancer (OC) is a refractory cancer that shows recurrence due to the acquisition of resistance to anticancer drugs, including cisplatin. However, the molecular mechanism underlying the acquisition of cisplatin resistance by cancer cells remains largely unknown. In the present study, two sets of ovarian endometrioid carcinoma cell lines were used: The parental A2780 cell line, the OVK18 cell line, and their derived cisplatin-resistant cells. It was found that cisplatin could induce ferroptosis in these parental cells by enhancing mitochondrial membrane potential and lipid peroxidation as assessed by flow cytometric analysis, and that expression of Ferredoxin1 (Fdx1), an iron-sulfur protein localized to the mitochondria, could be upregulated in cisplatin-resistant cells in the absence of cisplatin. Intriguingly, it was shown that the siRNA-mediated depletion of Fdx1 in cisplatin-resistant cells resulted in enhanced ferroptosis by increasing the mitochondrial membrane potential and lipid peroxidation induced by cisplatin. By examining Fdx1 expression with immunohistochemical analysis in clinical specimens from patients with OC, higher expression of Fdx1 was detected in cisplatin-resistant specimens than in cisplatin-sensitive specimens. Collectively, these results indicated that Fdx1 may be a novel and suitable diagnostic/prognostic marker and therapeutic molecular target for the treatment of cisplatin-resistant OC.