Department of Surgery, Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Surgery. 2011 Aug;150(2):284-98. doi: 10.1016/j.surg.2011.06.002.
The lipogenesis-promoting enzyme fatty acid synthase is highly expressed in pancreatic ductal adenocarcinoma. Angiotensin II, which is the principal hormone of the renin angiotensin system, is generated actively in the pancreas and has been shown to increase the expression of fatty acid synthase. The angiotensin II type 2 receptor has been proposed to play an important role in lipogenesis and fat deposition. In this study, we explored the potential role of the angiotensin II type 2 receptor in fatty acid synthase regulation in pancreatic ductal adenocarcinoma cells, and we evaluated the mechanisms involved.
Fatty acid synthase messenger RNA and protein in pancreatic ductal adenocarcinoma cell lines treated with or without angiotensin II (10(-6) to 10(-8) mol/L) in the presence or absence of the angiotensin II type 2 receptor blocker PD123319 (10(-4) to 10(-6) mol/L) were analyzed by real-time polymerase chain reaction and Western blotting. The total-AMP-activated protein kinase and phospho-AMP-activated protein kinase, total-acetyl CoA carboxylase and phospho-acetyl CoA carboxylase, and LKB1/STK11 were analyzed by Western immunoblotting. The tissue localization of the angiotensin II type 2 receptor was examined by immunohistochemistry in invasive pancreatic ductal adenocarcinoma lesions and matching normal tissue.
Angiotensin II type 2 receptor treatment increased fatty acid synthase expression and promoter activity in significantly pancreatic ductal adenocarcinoma cells; these effects were blocked significantly in the presence of PD123319. Interestingly, angiotensin II also induced angiotensin II type 2 receptor expression in pancreatic ductal adenocarcinoma cells. PD123319, C75, and AICAR decreased fatty acid synthase protein levels, but only PD123319 increased LKB1/STK11 levels. All 3 agents activated AMP-activated protein kinase differentially and inhibited acetyl CoA carboxylase. Angiotensin II type 2 receptor messenger RNA levels were upregulated significantly in 20 of the 25 neoplastic tissues examined (80%) when compared with matching controls. Angiotensin II type 2 receptor protein was localized in the malignant ducts and in the stromal cells.
Our data demonstrate a previously unknown involvement of the angiotensin II type 2 receptor in pancreatic ductal adenocarcinoma cell fatty acid synthesis and suggest that its blockade has potential as a novel chemopreventive and antilipogenic mechanism for human pancreatic ductal adenocarcinoma through the activation of AMP-activated protein kinase, which could have detrimental effects on cancer cell survival.
促进脂肪生成的酶脂肪酸合酶在胰腺导管腺癌中高度表达。血管紧张素 II 是肾素-血管紧张素系统的主要激素，在胰腺中大量产生，并已被证明能增加脂肪酸合酶的表达。血管紧张素 II 型 2 受体在脂肪生成和脂肪沉积中发挥重要作用。在这项研究中，我们探讨了血管紧张素 II 型 2 受体在胰腺导管腺癌细胞中调节脂肪酸合酶的潜在作用，并评估了相关机制。
用血管紧张素 II（10(-6) 至 10(-8) mol/L）处理胰腺导管腺癌细胞系，分析有无血管紧张素 II 型 2 受体阻滞剂 PD123319（10(-4) 至 10(-6) mol/L），采用实时聚合酶链反应和 Western 印迹法分析脂肪酸合酶信使 RNA 和蛋白。Western 免疫印迹法分析总-AMP 激活的蛋白激酶和磷酸化-AMP 激活的蛋白激酶、总乙酰辅酶 A 羧化酶和磷酸化乙酰辅酶 A 羧化酶、LKB1/STK11。用免疫组化法检测侵袭性胰腺导管腺癌病变和匹配的正常组织中血管紧张素 II 型 2 受体的组织定位。
血管紧张素 II 型 2 受体处理显著增加了胰腺导管腺癌细胞中脂肪酸合酶的表达和启动子活性；在 PD123319 存在下，这些作用明显被阻断。有趣的是，血管紧张素 II 也诱导胰腺导管腺癌细胞中血管紧张素 II 型 2 受体的表达。PD123319、C75 和 AICAR 降低脂肪酸合酶蛋白水平，但只有 PD123319 增加 LKB1/STK11 水平。所有 3 种药物均不同程度地激活 AMP 激活的蛋白激酶并抑制乙酰辅酶 A 羧化酶。与匹配对照相比，在 25 例肿瘤组织中，20 例（80%）显著上调了血管紧张素 II 型 2 受体的信使 RNA 水平。血管紧张素 II 型 2 受体蛋白定位于恶性导管和基质细胞中。
我们的数据表明，血管紧张素 II 型 2 受体以前未知地参与了胰腺导管腺癌细胞的脂肪酸合成，并表明通过激活 AMP 激活的蛋白激酶，其阻断具有作为人类胰腺导管腺癌的新型化学预防和抗脂生成机制的潜力，这可能对癌细胞存活产生不利影响。
