多巴胺D2受体介导三氟拉嗪对耐孕激素内膜癌细胞的增敏机制

It is well known that the dopamine receptor antagonist (Thioridazine and Trifluoperazine) can down-regulate the signal pathway of EGFR via dopamine receptor D2 (DRD2) subtype, then reverse the sensitivity of several drug-resistant cancer and inhibit the carcinogenesis. Moreover, higher level of EGFR means low level of PR-B subtype and low sensitivity of MPA for endometrial cancer. It is necessary to elucidate the mechanism of TFP on cross-talk between EGFR and PR, which regulate the sensitivity of MPA for endometrial cancer. In order to elucidate the biological functions, sensibilization mechanism of DRD2 and new therapeutic target, two kinds of endometrial cancer cells (with or without PR) were compared when the expression of DRD2 was inhibited or enhanced. With or without the trifluoperazine, the sensitivity of MPA for the tumor formation was analyzed to prove the mechanism of sensitization and new therapeutic target after the endometrial cancer cells were planted in the PRB gene knock-out C57BL/6 mice. The research will provide the new therapeutical theory on early endometrial cancer for fertility.

已知抗精神病药物（三氟拉嗪/甲硫哒嗪）可通过多巴胺D2受体（DRD2），下调表皮生长因子受体（EGFR）信号，恢复多种耐药癌细胞的药物敏感性。在证实EGFR的高表达可降低内膜癌细胞的孕激素（MPA）敏感性和孕激素受体（PR）B亚型的表达，以及三氟拉嗪能抑制耐药内膜癌细胞增殖的基础上，有必要明确三氟拉嗪调节MPA对内膜癌细胞的增敏机制。取MPA敏感和耐药（有或无PR表达）两类内膜癌细胞，抑制或增强DRD2表达，有或无三氟拉嗪作用下，比较MPA对细胞生物学功能、DRD2表达、激活EGFR等传导途径的差异。建立DRD2高/低表达的内膜癌细胞，种植于PR-B基因敲除的C57BL/6 小鼠皮下，或建立人内膜癌的裸鼠宫腔原位移植模型，分析三氟拉嗪和/或MPA抑制内膜癌生成的机制。阐明DRD2是否通过EGFR-PR交联机制介导耐药内膜癌细胞的增敏机制，为肿瘤与神经内分泌交叉学科的发展奠定理论基础。

已知抗精神病药物（三氟拉嗪/甲硫哒嗪）可通过多巴胺D2受体（DRD2），下调表皮生长因子受体（EGFR）信号，恢复多种耐药癌细胞的药物敏感性。在证实EGFR的高表达可降低内膜癌细胞的孕激素（MPA）敏感性和孕激素受体（PR）B亚型的表达，以及三氟拉嗪/甲硫哒嗪能抑制耐药内膜癌细胞增殖的基础上，有必要明确三氟拉嗪/甲硫哒嗪调节MPA对内膜癌细胞的增敏机制。甲硫哒嗪（Thio）对人内膜癌细胞（Ishikawa、HEC-1A）具有促凋亡作用，孕激素联合甲硫哒嗪通过捕获内膜癌细胞S及G2期，阻碍细胞周期的进展，提高孕激素对内膜癌细胞的促凋亡作用，同时甲硫哒嗪还可通过下调survivin、上调LC-3II 蛋白分子的表达，诱导内膜癌细胞发生自噬，从而改善内膜癌孕激素耐药细胞的敏感性，有望筛选针对耐药内膜癌的增敏药物，明确内膜癌耐药的分子机制和新的治疗靶点，为临床防治耐孕激素子宫内膜癌提供新的思路。内膜癌患者PR的表达与肿瘤的肌层浸润及病理分级呈正相关。IGF1R和EGFR与EC不良的临床病理特征有关，二者联合检测或能用于判断EC淋巴结转移。MPA可改变子宫内膜癌细胞lncRNAs与circRNAs表达谱，通过调解胰岛素代谢通路、细胞周期、p53信号通路等介导MPA的抗肿瘤作用。该研究有望为lncRNAs与circRNAs在子宫内膜癌孕激素治疗中的作用机制，及其作为孕激素疗效的潜在标志物提供理论依据。