WCU Biomodulation, Department of Agricultural Biotechnology, Seoul National University, Seoul, 08826, Republic of Korea.
Cancer Research Institute, College of Medicine, Seoul National University, Seoul, 03080, Republic of Korea.
Oncogene. 2019 Nov;38(45):7089-7105. doi: 10.1038/s41388-019-0949-5. Epub 2019 Aug 13.
Mitochondria undergo fission and fusion continually for survival through the course of cellular adaption processes in response to changes in the surrounding environment. Dysregulated mitochondrial dynamics has been reported in various diseases including cancer. Under hypoxic conditions (<1% O), the relationship between mitochondrial dynamics and sensitivity to cisplatin (CDDP) was examined in ovarian cancer cells. We found that hypoxia promoted mitochondrial fission and CDDP resistance in ovarian cancer cells. Hypoxia-induced reactive oxygen species (ROS) caused an increase in mitochondrial fission, a response abolished by free radical scavenging with N-acetylcysteine (NAC) and Trolox. Also, treatment of hydrogen peroxide (HO) decreased inhibitory p-Drp1 (Ser637) content and increased mitochondrial fission. Suppression of mitochondrial fission enhanced the CDDP sensitivity of hypoxic ovarian cancer cells. Lastly, in tumor spheroids from malignant ascites or tissues of patients with advanced-stage ovarian cancer, pretreatment with Mdivi-1 increased the CDDP sensitivity. Taken together, our results implicate that hypoxia-induced ROS trigger mitochondrial fission and CDDP resistance through downregulation of p-Drp1 (Ser637) and Mfn1 in ovarian cancer cells. Inhibition of Drp1 by Mdivi-1 treatment or si-Drp1 transfection increased CDDP sensitivity of ovarian cancer cells under hypoxia. Therefore, mitochondrial dynamics of cancer cells adapting to the hypoxic tumor microenvironment could be a potential target for anticancer therapy.
线粒体在细胞适应过程中不断经历分裂和融合，以应对周围环境的变化而存活。在包括癌症在内的各种疾病中，已经报道了线粒体动力学的失调。在缺氧条件下（<1% O），研究了卵巢癌细胞中线粒体动力学与顺铂（CDDP）敏感性之间的关系。我们发现，缺氧促进了卵巢癌细胞中线粒体的分裂和 CDDP 的耐药性。缺氧诱导的活性氧（ROS）引起线粒体分裂增加，用 N-乙酰半胱氨酸（NAC）和 Trolox 进行自由基清除可消除这种反应。此外，过氧化氢（HO）的处理降低了抑制性 p-Drp1（Ser637）的含量并增加了线粒体的分裂。抑制线粒体分裂增强了缺氧卵巢癌细胞对 CDDP 的敏感性。最后，在恶性腹水的肿瘤球体或晚期卵巢癌患者的组织中，用 Mdivi-1 预处理增加了 CDDP 的敏感性。总之，我们的结果表明，缺氧诱导的 ROS 通过下调 p-Drp1（Ser637）和 Mfn1 触发了卵巢癌细胞中的线粒体分裂和 CDDP 耐药性。用 Mdivi-1 处理或 si-Drp1 转染抑制 Drp1 增加了缺氧条件下卵巢癌细胞对 CDDP 的敏感性。因此，适应缺氧肿瘤微环境的癌细胞的线粒体动力学可能成为抗癌治疗的潜在靶点。
