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

Kota Arima, Masaki Ohmuraya, Keisuke Miyake, Mayu Koiwa, Tomoyuki Uchihara, Daisuke Izumi, Feng Gao, Atsuko Yonemura, Luke Bu, Hirohisa Okabe, Katsunori Imai, Daisuke Hashimoto, Yoshifumi Baba, Akira Chikamoto, Yo ichi Yamashita, Toru Furukawa, Kimi Araki, Hideo Baba, Takatsugu Ishimoto

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4 Citations (Scopus)

Abstract

The accumulation of prostaglandin E2 (PGE 2 ) during chronic inflammation has been implicated in the progression of several cancers. Cyclooxygenase is the key synthesizing enzyme of PGE 2 , 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 Kras LSL-G12D/+ ; Ptf1a Cre/+ (KC) mice. Furthermore, genetic deletion of 15-Pgdh in KC mice showed PGE 2 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.

Original languageEnglish
Pages (from-to)1211-1224
Number of pages14
JournalOncogene
Volume38
Issue number8
DOIs
Publication statusPublished - 2019 Feb 21

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Arima, K., Ohmuraya, M., Miyake, K., Koiwa, M., Uchihara, T., Izumi, D., Gao, F., Yonemura, A., Bu, L., Okabe, H., Imai, K., Hashimoto, D., Baba, Y., Chikamoto, A., Yamashita, Y. I., Furukawa, T., Araki, K., Baba, H., & Ishimoto, T. (2019). Inhibition of 15-PGDH causes Kras-driven tumor expansion through prostaglandin E2-ALDH1 signaling in the pancreas. Oncogene, 38(8), 1211-1224. https://doi.org/10.1038/s41388-018-0510-y