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Inhibition of 15-PGDH causes Kras-driven tumor expansion through prostaglandin E2-ALDH1 signaling in the pancreas

Oncogene volume 38, pages 1211–1224 (2019)Cite this article

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Abstract

The accumulation of prostaglandin E2 (PGE2) during chronic inflammation has been implicated in the progression of several cancers. Cyclooxygenase is the key synthesizing enzyme of PGE2, although the degradation enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) has received considerable attention recently. We investigated the molecular mechanisms of pancreatic ductal adenocarcinoma (PDAC) progression via 15-PGDH downregulation. Here, we found that 15-PGDH expression was inversely correlated with ALDH1, an important cancer stem cell-associated marker indicative of poor prognosis in humans. Moreover, we demonstrated that pharmacological inhibition of 15-PGDH enhanced CYP26A1 expression, leading to depletion of all-trans retinoic acid (ATRA) and expansion of the ALDH1-positive subset in both human PDAC cells and tumor cells of KrasLSL-G12D/+; Ptf1aCre/+ (KC) mice. Furthermore, genetic deletion of 15-Pgdh in KC mice showed PGE2 accumulation and ATRA depletion in the pancreas, resulting in PDAC with high levels of Aldh1 and Ki-67. Finally, ATRA replacement suppressed 15-PGDH inhibition-induced tumor progression in KC mice, and ATRA treatment attenuated Aldh1 activity in tumor cells isolated from the pancreas of 15-Pgdh−/− KC mice. These findings provide evidence that 15-PGDH inhibition enhances KRAS-driven tumor progression via ATRA depletion in the pancreas. Therefore, ATRA replacement could be a potential strategy for PDAC treatment.

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Acknowledgements

We are grateful to Dr. David A. Tuveson (Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA) for providing the KrasLSL-G12D mice and to Dr. Sanford D. Markowitz (Department of Medicine, Case Western Reserve University, Cleveland, OH, USA) for their kind advice about establishing 15-Pgdh−/− mice. This work was supported, in part, by the Japan Society for the Promotion of Science KAKENHI (Grant Numbers 16H06257, 16K15595, 17K16570, and 17K16571), Grant-in-Aid for JSPS Research Fellows (Grant Numbers 201860083), the Pancreas Research Foundation of Japan, the Kanae Foundation for the Promotion of Medical Science, the Yasuda Medical Foundation and the Shinnihon Foundation of Advanced Medical Treatment Research.

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Authors and Affiliations

  1. Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan

    Kota Arima, Keisuke Miyake, Tomoyuki Uchihara, Daisuke Izumi, Feng Gao, Atsuko Yonemura, Luke Bu, Hirohisa Okabe, Katsunori Imai, Daisuke Hashimoto, Yoshifumi Baba, Akira Chikamoto, Yo-ichi Yamashita, Hideo Baba & Takatsugu Ishimoto

  2. International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan

    Kota Arima, Keisuke Miyake, Mayu Koiwa, Tomoyuki Uchihara & Takatsugu Ishimoto

  3. Department of Genetics, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan

    Masaki Ohmuraya

  4. Department of Histopathology, Tohoku University Graduate School of Medicine, Sendai, Japan

    Toru Furukawa

  5. Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan

    Kimi Araki

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Contributions

Conception and design: Ko.A., H.B., T.I.; methodology development: Ko.A., M.O., K.M.; data acquisition: Ko.A., K.M., M.K., F.G., T.U, D.I., A.Y., L.B.; data analysis and interpretation: Ko.A., T.I.; manuscript writing and review: Ko.A., H.B., T.I.; administrative, technical, or material support: M.O., H.O., K.I., D.H., Y.B., A.C., Y.Y., T.F., Ki.A.; study supervision: M.O., T.F., Ki.A., H.B., T.I.

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Correspondence to Hideo Baba or Takatsugu Ishimoto.

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Arima, K., Ohmuraya, M., Miyake, K. et al. Inhibition of 15-PGDH causes Kras-driven tumor expansion through prostaglandin E2-ALDH1 signaling in the pancreas. Oncogene 38, 1211–1224 (2019). https://doi.org/10.1038/s41388-018-0510-y

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