Abstract 1694: Conjugated bile acids aggravate metastatic pancreatic cancer via sphingosine-1-phosphate receptor 2
Authors: Aoki Hiroaki , Aoki Masayo , Katsuta Eriko , Mukhopadhyay Partha , Yang Jing , Zhou Huiping , Spiegel Sarah , Takabe Kazuaki 
Published: July 2016

Abstract
Introduction: “Painless jaundice” is a classic sign of advanced pancreatic cancer, which is often times lethal. Bile drainage for obstructive jaundice by pancreatic cancer has been known to be clinically beneficial, however, the role of bile acids on pancreatic cancer biology has not been thoroughly investigated. We published that conjugated bile acids bind to sphingosine 1-phosphate receptor 2 (S1PR2) (Hepatology 2012) and regulate lipid metabolism in hepatocytes through SphK2 (Hepatology 2015). SphK1 and K2 are the enzymes that generate sphingosine-1-phosphate (S1P), a lipid mediator, which cause cell proliferation and migration via S1P receptors 1-5. We hypothesize that bile acid from obstructive jaundice aggravate the pancreatic cancer progression via S1PR2.
Method: Murine and human pancreatic cancer cell lines were used to examine growth response to CYM5520 (S1PR2 agonist), JTE-013 (S1PR2 antagonist), or FTY720 (functional antagonist of all S1P receptors except S1PR2). Obstructive jaundice model was made by total ligation of middle and left bile ducts with cholecystectomy, and Panc02-luc cells were implanted in the left lobe for liver metastasis, and intraperitoneally injected for carcinomatosis model.
Result: Stimulation by TCA or CYM5520 promoted Panc02-luc and AsPC-1 cell proliferation, which dominantly express S1PR2 among S1P receptors in dose dependent manner, but that was not the case in other cells (PANC-1, BxPC-3 and Miapaca-2) that express other S1P receptors. JTE-013 inhibited Panc02-luc and AsPC-1 cell growth, regardless of additional TCA stimulation. Treatment with FTY720 had no effect on S1P mediated Panc02-luc cell proliferation. Neither TCA nor CYM5520 was able to stimulate growth of Panc-1, BxPC-3, nor Miapaca-2. Obstructive jaundice significantly increased liver metastasis and carcinomatosis tumor burden, and significantly shortened survival. The role of S1P from the host was investigated by using Panc02-luc carcinomatosis model on SphK1 or SphK2 knockout mice. Unexpectedly, carcinomatosis progressed slower with less tumor burden in both SphK1 and K2 knockout mice and significantly prolonged survival compared with their littermate control wildtype. Significantly less proliferation, but no difference in apoptosis was seen in tumors in SphK1 knockout mice. Treatment by FTY720 to carcinomatosis of wildtype mice did not suppress cancer progression nor tumor burden.
Conclusion: Conjugated bile acids from obstructive jaundice aggravated metastatic pancreatic cancer via S1PR2, which is independent from host S1P.
Citation Format: Hiroaki Aoki, Masayo Aoki, Eriko Katsuta, Partha Mukhopadhyay, Jing Yang, Huiping Zhou, Sarah Spiegel, Kazuaki Takabe. Conjugated bile acids aggravate metastatic pancreatic cancer via sphingosine-1-phosphate receptor 2. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1694.