Integrative analyses of gene expression and chemosensitivity of patient-derived ovarian cancer spheroids link G6PD-driven redox metabolism to cisplatin chemoresistance.
Integrative analyses of gene expression and chemosensitivity of patient-derived ovarian cancer spheroids link G6PD-driven redox metabolism to cisplatin chemoresistance.
复制标题
对患者来源的卵巢癌球体的基因表达和化疗敏感性的综合分析将 G6PD 驱动的氧化还原代谢与顺铂化疗耐药性联系起来。
DOI：
10.1016/j.canlet.2021.08.018
复制
发表时间：
2021
期刊：
影响因子：
--
通讯作者：
*Okamoto K.
中科院分区：
文献类型：
--
作者：
Yamawaki K;Mori Y Sakai H;Kanda Y;Shiokawa D;Ueda U;Ishiguro T;Yoshihara K;Nagasaka K;Onda T;Kato T;Kondo T;Enomoto T;*Okamoto K.
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耐药性。在这里，我们已经建立了一个小组的患者来源的球体从卵巢癌的临床材料。使用治疗剂的系统评价表明，对铂基化合物的敏感性显着不同的球体。为了了解药物敏感性的分子基础，我们进行了综合分析，结合化疗耐药数据和基因表达谱的卵巢癌患者来源的球体。相关性分析显示，顺铂耐药与葡萄糖-6-磷酸脱氢酶（G6 PD）和谷胱甘肽产生的氧化还原酶水平升高显著相关。因此，体外建立的顺铂耐药球体显示G6 PD和活性谷胱甘肽水平升高。此外，G6 PD抑制剂联合顺铂治疗在体外抑制球状体增殖，并在很大程度上根除了小鼠异种移植模型中的腹膜转移。此外，G6 PD表达在癌变过程中升高，并与预后不良相关。因此，基因表达数据和化疗敏感性的结合揭示了G6 PD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。
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 establishedin vitroshowed elevated levels of G6PD and active glutathione. Moreover, treatment with a G6PD inhibitor in combination with cisplatin suppressed spheroid proliferationin vitroand 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.