HNF1β drives glutathione (GSH) synthesis underlying intrinsic carboplatin resistance of ovarian clear cell carcinoma (OCCC)
HNF1β drives glutathione (GSH) synthesis underlying intrinsic carboplatin resistance of ovarian clear cell carcinoma (OCCC)
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DOI：
10.1007/s13277-015-4290-5
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发表时间：
2016-04-01
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影响因子：
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通讯作者：
Serpa, Jacinta
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作者：
Lopes-Coelho, Filipa;Gouveia-Fernandes, Sofia;Serpa, Jacinta
对铂类化疗药物的耐药性是卵巢癌的一个一致特征;然而，尽管高级别浆液性癌（OSC）在化疗期间获得耐药性，但卵巢透明细胞癌（OCCC）具有内在耐药性。本研究的主要目的是探索，在体外和体内，如果肝细胞核因子1 β（HNF 1 β）和氨甲喋呤的耐药性的OCCC通过内在增加GSH的生物利用度作出贡献。为了揭示HNF 1 β的作用，还在不表达HNF 1 β的OSC细胞系中进行了实验。在ES 2细胞系（OCCC）和OVCAR 3细胞系（OSC）中评估代谢谱、GSH定量、HNF 1 β和γ-谷氨酰半胱氨酸连接酶催化亚基（GCLC）和修饰亚基（GCLM）表达、细胞周期和死亡;在ES 2中进行HNF 1 β敲低，并建立皮下和腹膜OCCC肿瘤的小鼠模型以测试丁硫克百威磺胺（BSO），作为卡铂的增敏剂谷氨酰胺分解在ES 2和OVCAR 3中被激活，尽管ES 2专门合成氨基酸和GSH。ES 2细胞比OVCAR 3对卡铂更耐药，并且BSO对GSH产生的消除使ES 2对卡铂敏感。HNF 1 β调节GCLC的表达，但不调节GCLM，因此调节ES 2中GSH的产生。在体内，卡铂之前的BSO显着降低皮下肿瘤的大小和GSH水平，以及腹膜传播。我们的研究揭示了HNF 1 β作为内在OCCC化疗耐药性的介导剂，并为重新探索使用BSO的癌症辅助治疗方法以克服OCCC缺乏有效治疗提供了线索。
Chemoresistance to platinum-based antineoplastic agents is a consistent feature among ovarian carcinomas; however, whereas high-grade serous carcinoma (OSC) acquires resistance during chemotherapy, ovarian clear cell carcinoma (OCCC) is intrinsically resistant. The main objective of this study was to explore, in vitro and in vivo, if hepatocyte nuclear factor 1 beta (HNF1 beta) and glutaminolysis contribute for the resistance of OCCC to carboplatin through the intrinsically increased GSH bioavailability. To disclose the role of HNF1 beta, experiments were also performed in an OSC cell line, which does not express HNF1 beta. Metabolic profiles, GSH quantification, HNF1 beta, and gamma-glutamylcysteine ligase catalytic subunit (GCLC) and modifier subunit (GCLM) expression, cell cycle, and death were assessed in ES2 cell line (OCCC) and OVCAR3 cell line (OSC); HNF1 beta knockdown was performed in ES2 and murine model of subcutaneous and peritoneal OCCC tumors was established to test buthionine sulphoxamine (BSO), as a sensitizer to carboplatin. Glutaminolysis is activated in ES2 and OVCAR3, though ES2 exclusively synthesizes amino acids and GSH. ES2 cells are more resistant to carboplatin than OVCAR3 and the abrogation of GSH production by BSO sensitizes ES2 to carboplatin. HNF1 beta regulates the expression of GCLC, but not GCLM, and consequently GSH production in ES2. In vivo, BSO prior to carboplatin reduces dramatically subcutaneous tumor size and GSH levels, as well as peritoneal dissemination. Our study discloses HNF1 beta as the mediator of intrinsic OCCC chemoresistance and sheds a light to re-explore a cancer adjuvant therapeutic approach using BSO to overcome the lack of efficient therapy in OCCC.