RRC ID 54134
Author 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 YI, Furukawa T, Araki K, Baba H, Ishimoto T.
Title Inhibition of 15-PGDH causes Kras-driven tumor expansion through prostaglandin E2-ALDH1 signaling in the pancreas.
Journal Oncogene
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.
Volume 38(8)
Pages 1211-1224
Published 2019-2-1
DOI 10.1038/s41388-018-0510-y
PII 10.1038/s41388-018-0510-y
PMID 30250298
MeSH Adenocarcinoma / drug therapy Adenocarcinoma / genetics* Adenocarcinoma / pathology Aldehyde Dehydrogenase 1 Family Animals Carcinoma, Pancreatic Ductal / drug therapy Carcinoma, Pancreatic Ductal / genetics* Carcinoma, Pancreatic Ductal / pathology Cell Line, Tumor Cell Proliferation / genetics Dinoprostone / genetics Disease Models, Animal Gene Expression Regulation, Neoplastic / drug effects Humans Hydroxyprostaglandin Dehydrogenases / genetics* Inflammation / genetics Inflammation / pathology Isoenzymes / genetics* Mice Neoplastic Stem Cells / metabolism Neoplastic Stem Cells / pathology Pancreas / drug effects Pancreas / metabolism Proto-Oncogene Proteins p21(ras) / genetics* Retinal Dehydrogenase / genetics* Retinoic Acid 4-Hydroxylase / genetics Tretinoin / administration & dosage
IF 7.971
Times Cited 4
Human and Animal Cells PANC-1(RCB2095) PK-8(RCB2700)