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Conjugated Bile Acids Accelerate Progression of Pancreatic Cancer Metastasis via S1PR2 Signaling in Cholestasis

  • Translational Research
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Abstract

Background

Pancreatic cancer (PC) has an extremely high mortality rate, where obstructive jaundice due to cholestasis is a classic symptom. Conjugated bile acids (CBAs) such as taurocholic acid (TCA) have been reported to activate both the ERK1/2 and AKT signaling pathways via S1P receptor 2 (S1PR2) and promote growth of cholangiocarcinoma. Thus, we hypothesize that CBAs, which accumulate in cholestasis, accelerate PC progression via S1PR2.

Methods

Murine Panc02-luc and human AsPC-1, MIA PaCa2, and BxPC-3 cells were treated with TCA, S1PR2 agonist CYM5520, S1PR2 antagonist JTE-013, sphingosine-1-phosphate (S1P), and functional S1P receptor antagonist (except S1PR2) FTY720. Bile duct ligation (BDL) was performed on liver implantation or intraperitoneal injection of Panc02-luc cells.

Results

Panc02-luc and AsPC-1 cells predominantly expressed S1PR2, and their growth and migration were stimulated by TCA or CYM5520 in dose-dependent manner, which was blocked by JTE-013. This finding was not seen in PC cell lines expressing other S1P receptors than S1PR2. Panc02-luc growth stimulation by S1P was not blocked by FTY720. BDL significantly increased PC liver metastasis compared with sham. PC peritoneal carcinomatosis was significantly worsened by BDL, confirmed by number of nodules, tumor weight, bioluminescence, Ki-67 stain, ascites, and worse survival compared with sham. CYM5520 significantly worsened PC carcinomatosis, whereas treatment with anti-S1P antibody or FTY720 also worsened progression.

Conclusions

CBAs accelerated growth of S1PR2 predominant PC both in vitro and in vivo. This finding implicates S1PR2 as a potential therapeutic target in metastatic S1PR2 predominant pancreatic cancer.

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Acknowledgement

None.

Funding

This research was supported by National Institutes of Health, USA Grant Nos. R01CA160688, R37CA248018, R01CA250412, R01CA251545, and R01EB029596, as well as US Department of Defense BCRP Grant Nos. W81XWH-19-1-0674 and W81XWH-19-1-0111 to K.T.; VA Merit Award I01BX004033, Research Career Scientist Award (IK6BX004477), VA ShEEP Grant (1 IS1 BX004777), National Institutes of Health Grant R01 DK104893 and R01DK-057543 to H.Z.; National Cancer Institute, cancer center support Grant P30CA016056 to Roswell Park Comprehensive Cancer Center.

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Author notes

  1. Joy Sarkar and Hiroaki Aoki have contributed equally to this work.

Authors and Affiliations

  1. Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY, USA

    Joy Sarkar MD, Rongrong Wu MD & Kazuaki Takabe MD, PhD

  2. Division of Surgical Oncology, Department of Surgery, Virginia Commonwealth University School of Medicine and Massey Cancer Center, Richmond, VA, USA

    Hiroaki Aoki MD, PhD, Masayo Aoki MD, PhD & Kazuaki Takabe MD, PhD

  3. Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan

    Hiroaki Aoki MD, PhD

  4. Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Masayo Aoki MD, PhD

  5. Department of Microbiology and Immunology, Virginia Commonwealth University School of Medicine and, McGuire VA Medical Center, Richmond, VA, USA

    Phillip Hylemon PhD & Huiping Zhou PhD

  6. Department of Surgery, University at Buffalo Jacob School of Medicine and Biomedical Sciences, The State University of New York, Buffalo, NY, USA

    Kazuaki Takabe MD, PhD

  7. Department of Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

    Kazuaki Takabe MD, PhD

  8. Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo, Japan

    Kazuaki Takabe MD, PhD

  9. Department of Surgery, Yokohama City University, Yokohama, Japan

    Kazuaki Takabe MD, PhD

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  1. Joy Sarkar MD
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Sarkar, J., Aoki, H., Wu, R. et al. Conjugated Bile Acids Accelerate Progression of Pancreatic Cancer Metastasis via S1PR2 Signaling in Cholestasis. Ann Surg Oncol 30, 1630–1641 (2023). https://doi.org/10.1245/s10434-022-12806-4

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