H. Aoki1,2, M. Aoki1,2, E. Katsuta1,2, L. J. Fernandez1, P. Mukhopadhyay1,2, J. Yang3, H. Zhou3, S. Spiegel2, K. Takabe1,2 1Virginia Commonwealth University,Division Of Surgical Oncology, Department Of Surgery,Richmond, VA, USA 2Virginia Commonwealth University,Department Of Biochemistry & Molecular Biology,Richmond, VA, USA 3Virginia Commonwealth University,Department Of Microbiology And Immunology,Richmond, VA, USA
Introduction: Pancreatic cancer (PC) remains one of the deadliest types of cancers. Despite the recent improvement in survival of patients with small resectable tumors, prognosis of unresectable PC that collectively represents over 80% of individuals remains dismal with the 5-year survival of 5% and median survival is within ten months. The classical clinical sign of pancreatic head cancer is painless jaundice. There have been numerous publications regarding the clinical benefit of bile drainage in obstructive jaundice, however, the effect of it on pancreatic cancer biology, such as tumor growth, has never been thoroughly investigated. We have recently published that conjugated bile acids (CBAs) binds to sphingosine 1-phosphate receptor 2 (S1PR2), and it activate nuclear SphK2 that epigentically regulate gene expression (Nagahashi, Takabe, Zhou et al, Hepatology 2015). Indeed, it was reported that CBAs promote growth of cholangiocarcinoma through S1PR2. Thus, we hypothesized that CBAs from obstructive jaundice aggravate the pancreatic cancer progression via S1PRs.
Method: Expression of S1P receptors (S1PR1-5) in murine (panc02-luc) and human (MiaPaca-2) pancreatic cancer cell lines were determined by real-time RT-PCR. Cells were treated with CBAs with or without JTE-013 (S1PR2 antagonist) and viable cells were quantified using WST-8. Panc02-luc cells were implanted in the left lobe of the liver of C57/Bl6 mice with or without obstructive jaundice, created by left and middle bile duct ligation with cholecystectomy. Tumor burden was quantified using bioluminescence imaging on the indicated days and tumors were harvested on day 18.
Result: Hielarchial cluster analysis of pancreatic adenocarcinoma in The Cancer Genome Atlas (N=183) demonstrated that S1PR2, S1PR5 and SphK1 gene expressions have strong positive correlations. Among 5 S1P receptors, S1PR2 is the only one expressed in panc02-luc cells and S1PR2 and S1PR5 are expressed in MiaPaca-2 cells. CBA-mediated cell growth was inhibited by JTE-013, but JTE-013 alone was also found to be growth inhibitory even in the absence of CBA. In obstructive jaundice mice group, significant increase in tumor burden was observed by bioluminescence. Left lobe+tumor / body weight ratio was significantly larger in obstructive jaundice group.
Conclusion: Conjugated bile acid signaling via S1PR2 promotes pancreatic cancer cell growth. Obstructive jaundice aggravated pancreatic cancer, and further study is warranted to investigate the possibility of targeting S1PR2 as a potential new therapeutic for pancreatic cancer treatment.