Department of Gynecology and Obstetrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Department of Genome Analysis, Institute of Biomedical Science, Kansai Medical University, Hirakata, Japan.
Cancer Sci. 2021 Nov;112(11):4627-4640. doi: 10.1111/cas.15125. Epub 2021 Sep 13.
Ovarian clear cell carcinoma (CCC) exhibits an association with endometriosis, resistance to oxidative stress, and poor prognosis owing to its resistance to conventional platinum-based chemotherapy. A greater understanding of the molecular characteristics and pathogenesis of ovarian cancer subtypes may facilitate the development of targeted therapeutic strategies, although the mechanism of drug resistance in ovarian CCC has yet to be determined. In this study, we assessed exome sequencing data to identify new therapeutic targets of mitochondrial function in ovarian CCC because of the central role of mitochondria in redox homeostasis. Copy number analyses revealed that chromosome 17q21-24 (chr.17q21-24) amplification was associated with recurrence in ovarian CCC. Cell viability assays identified an association between cisplatin resistance and chr.17q21-24 amplification, and mitochondrion-related genes were enriched in patients with chr.17q21-24 amplification. Patients with high expression of pyruvate dehydrogenase kinase 2 (PDK2) had a worse prognosis than those with low PDK2 expression. Furthermore, inhibition of PDK2 synergistically enhanced cisplatin sensitivity by activating the electron transport chain and by increasing the production of mitochondrial reactive oxygen species. Mouse xenograft models showed that inhibition of PDK2 with cisplatin inhibited tumor growth. This evidence suggests that targeting mitochondrial metabolism and redox homeostasis is an attractive therapeutic strategy for improving drug sensitivity in ovarian CCC.
卵巢透明细胞癌（CCC）与子宫内膜异位症有关，由于其对传统铂类化疗的耐药性，表现出对氧化应激的抗性和不良预后。对卵巢癌亚型的分子特征和发病机制有更深入的了解，可能有助于开发靶向治疗策略，尽管卵巢 CCC 耐药的机制尚未确定。在这项研究中，我们评估了外显子组测序数据，以确定卵巢 CCC 中线粒体功能的新治疗靶点，因为线粒体在氧化还原平衡中起着核心作用。拷贝数分析显示，染色体 17q21-24（chr.17q21-24）扩增与卵巢 CCC 的复发有关。细胞活力测定确定了顺铂耐药性与 chr.17q21-24 扩增之间的关联，并且与 chr.17q21-24 扩增相关的线粒体相关基因在患者中富集。丙酮酸脱氢酶激酶 2（PDK2）高表达的患者预后比 PDK2 低表达的患者差。此外，通过激活电子传递链和增加线粒体活性氧的产生，PDK2 的抑制协同增强了顺铂的敏感性。小鼠异种移植模型表明，用顺铂抑制 PDK2 可抑制肿瘤生长。这一证据表明，靶向线粒体代谢和氧化还原平衡是提高卵巢 CCC 药物敏感性的一种有吸引力的治疗策略。
