Journal Article

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

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

2019

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 15-Hydroxyprostaglandin dehydrogenase (NAD+) / 42/89 / 45/90 / 631/67/1504/1713 / 631/67/70 / 64/110 / 64/60 / 82/51 / 82/58 / 96/1 / 96/31 / 96/44 / Adenocarcinoma / Adenocarcinoma - drug therapy / Adenocarcinoma - genetics / Adenocarcinoma - pathology / Aldehyde Dehydrogenase 1 Family / Animals / Apoptosis / Carcinoma, Pancreatic Ductal - drug therapy / Carcinoma, Pancreatic Ductal - genetics / Carcinoma, Pancreatic Ductal - pathology / Care and treatment / Cell Biology / Cell Line, Tumor / Cell Proliferation - genetics / Cellular signal transduction / Clonal deletion / COX-2 inhibitors / Cytochrome P-450 / Development and progression / Dinoprostone - genetics / Disease Models, Animal / Enzymes / Gene expression / Gene Expression Regulation, Neoplastic - drug effects / Genetic aspects / Health aspects / Human Genetics / Humans / Hydroxyprostaglandin Dehydrogenases - genetics / Inflammation / Inflammation - genetics / Inflammation - pathology / Internal Medicine / Isoenzymes - genetics / K-Ras protein / Medicine / Medicine & Public Health / Mice / Molecular modelling / Neoplastic Stem Cells - metabolism / Neoplastic Stem Cells - pathology / Oncology / Oxidoreductases / Pancreas / Pancreas - drug effects / Pancreas - metabolism / Pancreatic cancer / Pancreatic tumors / Prostaglandin E2 / Prostaglandin endoperoxide synthase / Prostaglandins / Prostaglandins E / Proto-Oncogene Proteins p21(ras) - genetics / Retinal Dehydrogenase - genetics / Retinoic acid / Retinoic Acid 4-Hydroxylase - genetics / Stem cells / Tretinoin / Tretinoin - administration & dosage / Tumor cells / Tumors