Ovarian cancer is an aggressive disease that affects about 300,000 patients worldwide, with a yearly death count of about 185,000. Following surgery, treatment involves adjuvant or neoadjuvant administration of taxane with platinum compounds cisplatin or carboplatin, which alkylate DNA through the same chemical intermediates. However, although platinum-based therapy can cure patients in a number of cases, a majority of them discontinues treatment owing to side effects and to the emergence of resistance. In this study, we focused on resistance to cisplatin and investigated whether metabolic changes could be involved. As models, we used matched pairs of cisplatin-sensitive (SKOV-3 and COV-362) and cisplatin-resistant (SKOV-3-R and COV-362-R) human ovarian carcinoma cells that were selected in vitro following exposure to increasing doses of the chemotherapy. Metabolic comparison revealed that resistant cells undergo a shift toward a more oxidative metabolism. The shift goes along with a reorganization of the mitochondrial network, with a generally increased mitochondrial compartment. More functional mitochondria in cisplatin-resistant compared with cisplatin-sensitive cells were associated to enzymatic changes affecting either the electron transport chain (SKOV-3/SKOV-3-R model) or mitochondrial coupling (COV-362/COV-362-R model). Our findings further indicate that the preservation of functional mitochondria in these cells could be due to an increased mitochondrial turnover rate, suggesting mitophagy inhibition as a potential strategy to tackle cisplatin-resistant human ovarian cancer progression. Implications: Besides classical mechanisms related to drug efflux and target modification, we report that preserving functional mitochondria is a strategy used by human ovarian cancer cells to resist to cisplatin chemotherapy.

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线粒体参与人卵巢癌细胞对顺铂的耐药性

卵巢癌是一种侵袭性疾病，影响全球约 300,000 名患者，每年的死亡人数约为 185,000。手术后，治疗涉及紫杉烷与铂化合物顺铂或卡铂的辅助或新辅助给药，它们通过相同的化学中间体使 DNA 烷基化。然而，尽管基于铂的治疗可以治愈许多患者，但大多数患者由于副作用和耐药性的出现而停止治疗。在这项研究中，我们专注于对顺铂的耐药性，并调查是否可能涉及代谢变化。作为模特，我们使用匹配的顺铂敏感（SKOV-3 和 COV-362）和顺铂抗性（SKOV-3-R 和 COV-362-R）人卵巢癌细胞，这些细胞在暴露于增加剂量的化疗。代谢比较显示抗性细胞经历了向更多氧化代谢的转变。这种转变伴随着线粒体网络的重组，线粒体室普遍增加。与顺铂敏感细胞相比，顺铂抗性细胞中功能更多的线粒体与影响电子传递链（SKOV-3/SKOV-3-R 模型）或线粒体偶联（COV-362/COV-362-R 模型）的酶变化有关）。我们的研究结果进一步表明，这些细胞中功能性线粒体的保留可能是由于线粒体更新率增加，这表明抑制线粒体自噬是解决顺铂耐药的人类卵巢癌进展的潜在策略。启示：除了与药物外排和靶标修饰相关的经典机制外，我们还报告说，保留功能性线粒体是人类卵巢癌细胞用来抵抗顺铂化疗的一种策略。