脂肪酸受体GPR120调控细胞药物外泵和DNA修复致肿瘤多药耐药的作用及机制

Chemotherapy is one of the most widely used treatments of the malignant tumor, while its failure chiefly because the multidrug resistance (MDR) of tumor cells. The mechanism of MDR formation is so complicated that till now little is known about. Recent researches show that the abnormally increase of unsaturated fatty acid can induce MDR formation. And our previous study found that GPR120, a receptor of unsaturated fatty acid, whose activation can activate calcium channel and the PI3K/Akt signaling pathway, plays an important role in tumor survival. According to these findings, we speculated that unsaturated fatty acids may regulate MDR of tumor cells by activating GPR120. On the basis of the previous work and with breast carcinoma MDR as a pointcut, our project group plans to further systematically research and establish the mechanism that how fatty acid activates GPR120 and then results in breast cancer MDR: A, make clear the correlation between GPR120 activation and MDR. B, discuss how GPR120 regulates the expression of tumor cell drug pump P – gp and DNA repair capacity. C, figure out the mechanism of GPR120 activation and study the experimental intervention strategy. D, with neoadjuvant chemotherapy of breast carcinoma as a point of penetration, studies the correlation between the Clinicopathological features/prognosis of breast cancer and chemotherapeutic effect. Thus, based on these researches, we can provide new theoretical breakthrough and countermeasures for establishing a system that predict chemotherapy effect and choose reasonably individualized chemotherapy regimens as well as a new strategy that reverse MDR with GPR120 as breakthrough point.

化疗是目前恶性肿瘤治疗中应用最广的手段之一，而肿瘤细胞多药耐药性（MDR）是导致肿瘤化疗失败的首要原因。MDR形成机制十分复杂且目前已有认识相对局限，亟待理论突破。近年发现，肿瘤微环境中部分脂肪酸异常升高可诱导肿瘤MDR。我们前期研究发现GPR120作为此类脂肪酸的受体，活化后可开启Ca2+泵及PI3K/Akt信号，促进肿瘤存活，推测此类脂肪酸可能通过激活GPR120调控肿瘤MDR。为此项目组在前期工作基础上，拟进一步以乳腺癌MDR为切入点，系统研究并确立脂肪酸活化GPR120致乳腺癌MDR的作用机制：探讨GPR120调控药泵P-gp表达和DNA修复能力的机制；明析GPR120活化机制；探究GPR120与乳腺癌患者化疗疗效、预后及复发的相关性；开展实验性干预策略研究。藉此为建立预测化疗效果和合理个体化化疗方案系统及靶向GPR120逆转MDR新策略提供新的理论突破。

本研究利用新辅助化疗乳腺癌患者的穿刺病理标本，通过分析GPR120表达水平与新辅助化疗反应的相关性，发现高表达GPR120的患者新辅助化疗效果差。GPR120激动GW9508刺激乳腺癌细胞MCF-7、T47-D，能够明显增加细胞对表霉素的耐药性，表现为半数抑制浓度IC50的增加，而GPR120拮抗剂或敲减GPR120可逆转这一效应。GPR120活化一方面促进ABC转运蛋白和DNA核苷酸切除修复酶的表达，增加化疗药物外排，降低化疗药物的毒性作用；另一方面上调脂肪酸水平，进一步诱导GPR120活化的正反馈通路。利用拮抗剂AH7614或GPR120-SiRNA阻断GPR120活化联合化疗药物能够明显抑制乳腺癌耐药细胞MCF-7/ADM裸鼠移植瘤的生长。本研究确立了 GPR120 在乳腺癌生物学中的作用，并显示了其作为乳腺癌耐药治疗策略新靶标的潜能。