GLP-1R信号通路调节NF-κB/ABCG2在胰腺癌化疗耐药中的作用及机制研究

It is crucial for pancreatic cancer patients with diabetes to select hypoglycemic drugs suitably. In recent years, GLP-1-based therapies have been widely used as the optimal treatment options for diabetes. Our previous studies first reported that GLP-1R pathway activation by liraglutide inhibited growth and metastasis in pancreatic cancer cells mediated by PI3K/Akt/NF-κB pathway. NF-κB is well known to play a key role in cancer chemoresistance through regulating multiresistance gene ABCG2. As such, it is unclear whether GLP-1R pathway activation could reverse chemoresistance in pancreatic cancer. Our preliminary studies showed that the levels of GLP-1R expression in chemoresistant cell lines of pancreatic cancer were lower than normal pancreatic cancer; GLP-1R pathway activation inhibited cancer cell growth as results of the inhibitory effect on NF-κB and subsequent ABCG2. Therefore, we intend to further investigate the effect and mechanism of GLP-1R pathway on chemoresistance of pancreatic cancer by regulation of NF-κB/ABCG2 using siRNA, eukaryotic expression vector, EMSA, ChIP and other methods. This project will provide scientific evidence for seeking molecular targets on reversal of chemoresistance, as well as new ideas for treating pancreatic cancer patients with diabetes.

对于胰腺癌合并糖尿病患者，降糖药物的优化选择至关重要。GLP-1类药物作为新型降糖药已被广泛应用。我们既往首次报道了该类药物能够激活人胰腺癌细胞GLP-1R信号通路，抑制PI3K/Akt/NF-κB介导的肿瘤生长和转移。业已证实，NF-κB通过调控耐药基因ABCG2在肿瘤化疗耐药中发挥重要作用。那么GLP-1R激活能否逆转胰腺癌的化疗耐药性？预实验显示，耐药细胞株中GLP-1R表达降低，而激活GLP-1R能够下调NF-κB/ABCG2表达，抑制耐药细胞株的生长。据此，我们提出假设：GLP-1R激活后下调NF-κB，抑制其转录激活ABCG2，最终逆转胰腺癌化疗耐药性。本项目拟采用siRNA、真核表达载体、EMSA、ChIP等方法阐明GLP-1R信号通路调节NF-κB/ABCG2在胰腺癌化疗耐药中的作用及机制，为寻找逆转胰腺癌化疗耐药的靶点提供科学依据，为胰腺癌合并糖尿病患者提供新的治疗思路。

胰腺癌与糖尿病密切相关。糖尿病不仅是胰腺癌的危险因素，而且是胰腺癌的临床表现之一。血糖控制状况影响胰腺癌患者预后，长期高血糖状态是预后不良的因素。因此，在胰腺癌合并糖尿病的患者中优化选择降糖药物具有重要的临床意义。近年来，GLP-1类药物作为新型降糖药已被广泛应用。我们既往首次报道了该类药物能够激活人胰腺癌细胞GLP-1R/cAMP/PKA信号通路，抑制PI3K/Akt/NF-κB介导的肿瘤生长和转移。业已证实，化疗在胰腺癌的综合治疗中发挥着重要作用，而先天性和获得性耐药是化疗失败的主要原因。本研究进一步阐明了GLP-1类药物在胰腺癌化疗耐药中的作用及分子机制。本研究显示，胰腺癌耐药细胞株中GLP-1R/cAMP/PKA信号通路表达下调，GLP-1类药物利拉鲁肽可以激活胰腺癌耐药细胞株中GLP-1R/cAMP/PKA信号通路，下调其下游耐药基因NF-κB的表达，进而抑制其转录激活ABCG2，抑制耐药细胞的增殖和促进耐药细胞的凋亡，最终逆转胰腺癌化疗耐药性。为了进一步验证上述结论，本研究在胰腺癌细胞体外实验和动物体内实验中同样证明了利拉鲁肽与吉西他滨联合用药可以发挥协同抑癌作用，利拉鲁肽增强了胰腺癌细胞对吉西他滨的化疗敏感性。因此，本研究阐明了对于胰腺癌合并糖尿病的患者，应用GLP-1类药物控制血糖的同时对胰腺癌的治疗是有益的，特别是对于吉西他滨耐药的胰腺癌患者，GLP-1类药物能够增强其化疗敏感性。本研究为寻找逆转胰腺癌化疗耐药的靶点提供科学依据，为胰腺癌合并糖尿病患者提供新的治疗思路。