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Integrative analyses of gene expression and chemosensitivity of patient-derived ovarian cancer spheroids link G6PD-driven redox metabolism to cisplatin chemoresistance
Cancer Letters ( IF 9.7 ) Pub Date : 2021-08-19 , DOI: 10.1016/j.canlet.2021.08.018
Kaoru Yamawaki 1 , Yutaro Mori 1 , Hiroaki Sakai 2 , Yusuke Kanda 2 , Daisuke Shiokawa 2 , Haruka Ueda 3 , Tatsuya Ishiguro 3 , Kosuke Yoshihara 3 , Kazunori Nagasaka 4 , Takashi Onda 5 , Tomoyasu Kato 6 , Tadashi Kondo 7 , Takayuki Enomoto 3 , Koji Okamoto 2
Affiliation  

Patient-derived cells and xenografts retain the biological characteristics of clinical cancers and are instrumental in gaining a better understanding of the chemoresistance of cancer cells. Here, we have established a panel of patient-derived spheroids from clinical materials of ovarian cancer. Systematic evaluation using therapeutic agents indicated that sensitivity to platinum-based compounds significantly varied among the spheroids. To understand the molecular basis of drug sensitivity, we performed integrative analyses combining chemoresistance data and gene expression profiling of the ovarian cancer patient-derived spheroids. Correlation analyses revealed that cisplatin resistance was significantly associated with elevated levels of glucose-6-phosphate dehydrogenase (G6PD) and glutathione-producing redox enzymes. Accordingly, cisplatin-resistant spheroids established in vitro showed elevated levels of G6PD and active glutathione. Moreover, treatment with a G6PD inhibitor in combination with cisplatin suppressed spheroid proliferation in vitro and largely eradicated peritoneal metastasis in mouse xenograft models. Furthermore, G6PD expression was elevated during carcinogenesis and associated with poor prognosis. Thus, the combination of gene expression data and chemosensitivity revealed the essential roles of G6PD-driven redox metabolism in cisplatin resistance, underscoring the significance of an integrative approach using patient-derived cells.



中文翻译:

患者来源的卵巢癌球体基因表达和化学敏感性的综合分析将 G6PD 驱动的氧化还原代谢与顺铂化学抗性联系起来

患者来源的细胞和异种移植物保留了临床癌症的生物学特征,有助于更好地了解癌细胞的化学抗性。在这里,我们从卵巢癌的临床材料中建立了一组患者来源的球体。使用治疗剂的系统评估表明,不同球体对铂类化合物的敏感性存在显着差异。为了了解药物敏感性的分子基础,我们结合化学抗性数据和卵巢癌患者来源球体的基因表达谱进行了综合分析。相关性分析表明,顺铂耐药性与葡萄糖 6-磷酸脱氢酶 (G6PD) 和产生谷胱甘肽的氧化还原酶水平升高显着相关。因此,体外显示 G6PD 和活性谷胱甘肽水平升高。此外,用 G6PD 抑制剂联合顺铂治疗在体外抑制球体增殖并在很大程度上根除小鼠异种移植模型中的腹膜转移。此外,G6PD 表达在致癌过程中升高并与不良预后相关。因此,基因表达数据和化学敏感性的结合揭示了 G6PD 驱动的氧化还原代谢在顺铂耐药中的重要作用,强调了使用患者来源细胞的综合方法的重要性。

更新日期:2021-08-21
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