Chemoresistance gradually develops during treatment of epithelial ovarian cancer (EOC). Metabolic alterations, especially in vivo easily detectable metabolites in paclitaxel (PTX)-resistant EOC remain unclear. Xenograft models of the PTX-sensitive and PTX-resistant EOCs were built. Using a combination of in vivo proton-magnetic resonance spectroscopy (1H-MRS), metabolomics and proteomics, we investigated the in vivo metabolites and dysregulated metabolic pathways in the PTX-resistant EOC. Furthermore, we analyzed the RNA expression to validate the key enzymes in the dysregulated metabolic pathway. On in vivo 1H-MRS, the ratio of (glycerophosphocholine + phosphocholine) to (creatine + phosphocreatine) ((GPC + PC) to (Cr + PCr))(i.e. Cho/Cr) in the PTX-resistant tumors (1.64 [0.69, 4.18]) was significantly higher than that in the PTX-sensitive tumors (0.33 [0.10, 1.13]) (P = 0.04). Forty-five ex vivo metabolites were identified to be significantly different between the PTX-sensitive and PTX-resistant tumors, with the majority involved of lipids and lipid-like molecules. Spearman’s correlation coefficient analysis indicated in vivo and ex vivo metabolic characteristics were highly consistent, exhibiting the highest positive correlation between in vivo GPC + PC and ex vivo GPC (r = 0.885, P < 0.001). These metabolic data suggested that abnormal choline concentrations were the results from the dysregulated glycerophospholipid metabolism, especially choline metabolism. The proteomics data indicated that the expressions of key enzymes glycerophosphocholine phosphodiesterase 1 (GPCPD1) and glycerophosphodiester phosphodiesterase 1 (GDE1) were significantly lower in the PTX-resistant tumors compared to the PTX-sensitive tumors (both P < 0.01). Decreased expressions of GPCPD1 and GDE1 in choline metabolism led to an increased GPC levels in the PTX-resistant EOCs, which was observed as an elevated total choline (tCho) on in vivo 1H-MRS. These findings suggested that dysregulated choline metabolism was associated with PTX-resistance in EOCs and the elevated tCho on in vivo 1H-MRS could be as an indicator for the PTX-resistance in EOCs.

中文翻译：

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质子磁共振波谱在体内检测紫杉醇耐药卵巢癌胆碱代谢失调

在上皮性卵巢癌 (EOC) 的治疗过程中逐渐产生化疗耐药性。代谢改变，尤其是体内容易检测到的紫杉醇 (PTX) 耐药 EOC 中的代谢物仍不清楚。建立了 PTX 敏感和 PTX 抗性 EOC 的异种移植模型。我们结合体内质子磁共振波谱 (1H-MRS)、代谢组学和蛋白质组学，研究了 PTX 抗性 EOC 中的体内代谢物和失调的代谢途径。此外，我们分析了 RNA 表达以验证失调代谢途径中的关键酶。在体内 1H-MRS 上，PTX 耐药肿瘤中 (甘油磷酸胆碱 + 磷酸胆碱) 与 (肌酸 + 磷酸肌酸) ((GPC + PC) 与 (Cr + PCr)) 的比值 (即 Cho/Cr) (1.64 [0.69 , 4. 18]) 显着高于 PTX 敏感肿瘤 (0.33 [0.10, 1.13]) (P = 0.04)。45 种离体代谢物在 PTX 敏感和 PTX 抗性肿瘤之间被确定为显着不同，其中大多数涉及脂质和脂质样分子。Spearman 相关系数分析表明，体内和体外代谢特征高度一致，体内 GPC + PC 和体外 GPC 之间的正相关性最高（r = 0.885，P < 0.001）。这些代谢数据表明，胆碱浓度异常是甘油磷脂代谢异常，尤其是胆碱代谢异常的结果。蛋白质组学数据表明，与对 PTX 敏感的肿瘤相比，PTX 耐药肿瘤中关键酶甘油磷酸胆碱磷酸二酯酶 1 (GPCPD1) 和甘油磷酸二酯磷酸二酯酶 1 (GDE1) 的表达显着降低（均 P < 0.01）。GPCPD1 和 GDE1 在胆碱代谢中的表达降低导致 PTX 抗性 EOCs 中 GPC 水平升高，观察到体内 1H-MRS 上总胆碱 (tCho) 升高。这些发现表明，胆碱代谢失调与 EOCs 中的 PTX 抗性有关，体内 1H-MRS 上升高的 tCho 可作为 EOCs 中 PTX 抗性的指标。GPCPD1 和 GDE1 在胆碱代谢中的表达降低导致 PTX 抗性 EOCs 中 GPC 水平升高，观察到体内 1H-MRS 上总胆碱 (tCho) 升高。这些发现表明，胆碱代谢失调与 EOCs 中的 PTX 抗性有关，体内 1H-MRS 上升高的 tCho 可作为 EOCs 中 PTX 抗性的指标。GPCPD1 和 GDE1 在胆碱代谢中的表达降低导致 PTX 抗性 EOCs 中 GPC 水平升高，观察到体内 1H-MRS 上总胆碱 (tCho) 升高。这些发现表明，胆碱代谢失调与 EOCs 中的 PTX 抗性有关，体内 1H-MRS 上升高的 tCho 可作为 EOCs 中 PTX 抗性的指标。