Angiotensin II type 2 receptor blockade inhibits fatty acid synthase production through activation of AMP-activated protein kinase in pancreatic cancer cells.

BACKGROUND

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.

METHODS

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.

RESULTS

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.

CONCLUSION

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.