Regional differences in prostaglandin E2 metabolism in human colorectal cancer liver metastases

Abstract

BackgroundProstaglandin (PG) E2 plays a critical role in colorectal cancer (CRC) progression, including epithelial-mesenchymal transition (EMT). Activity of the rate-limiting enzyme for PGE2 catabolism (15-hydroxyprostaglandin dehydrogenase [15-PGDH]) is dependent on availability of NAD+. We tested the hypothesis that there is intra-tumoral variability in PGE2 content, as well as in levels and activity of 15-PGDH, in human CRC liver metastases (CRCLM). To understand possible underlying mechanisms, we investigated the relationship between hypoxia, 15-PGDH and PGE2 in human CRC cells in vitro.MethodsTissue from the periphery and centre of 20 human CRCLM was analysed for PGE2 levels, 15-PGDH and cyclooxygenase (COX)-2 expression, 15-PGDH activity, and NAD+/NADH levels. EMT of LIM1863 human CRC cells was induced by transforming growth factor (TGF) β.ResultsPGE2 levels were significantly higher in the centre of CRCLM compared with peripheral tissue (P = 0.04). There were increased levels of 15-PGDH protein in the centre of CRCLM associated with reduced 15-PGDH activity and low NAD+/NADH levels. There was no significant heterogeneity in COX-2 protein expression. NAD+ availability controlled 15-PGDH activity in human CRC cells in vitro. Hypoxia induced 15-PGDH expression in human CRC cells and promoted EMT, in a similar manner to PGE2. Combined 15-PGDH expression and loss of membranous E-cadherin (EMT biomarker) were present in the centre of human CRCLM in vivo.ConclusionsThere is significant intra-tumoral heterogeneity in PGE2 content, 15-PGDH activity and NAD+ availability in human CRCLM. Tumour micro-environment (including hypoxia)-driven differences in PGE2 metabolism should be targeted for novel treatment of advanced CRC.

15-Deoxy-Δ12,14-prostaglandin J2 Induces Epithelial-tomesenchymal Transition in Human Breast Cancer Cells and Promotes Fibroblast Activation

“…Contrary to our speculation, however, PGE 2 did not induce EMT of human breast cancer (MCF-7) cells. It has been shown that the level of PGE 2 is different between the central and peripheral regions of colorectal cancer [22]. Similarly, the function of PGE 2 may also differ depending on its subcellular localization.…”

Downregulation of 15-hydroxyprostaglandin dehydrogenase during acquired tamoxifen resistance and association with poor prognosis in ERα-positive breast cancer

“…Both assays were performed using previously protocols published [ 26 ]. For PGE 2 , serum-free conditioned medium was collected from cells after overnight incubation, and PGE 2 levels were measured using a competitive immunoassay (Amersham Biosciences, UK), and normalised to total cellular protein content as measured by Bradford assay.…”

“…Following ethical approval (06/Q1206/180) we investigated HPGD expression in 350 primary invasive breast cancers, all of which, had been surgically resected and received adjuvant TAM, and were represented on tissue microarrays (TMAs) [24,29] . Tumour staining was achieved using previously described methods [24,26].…”

NS-398 promotes pancreatic cancer cell invasion by CD147 and MMP-2 via the activation of P38

“…COX-1 is constitutively expressed in several tissues and is responsible for various physiological functions, whereas COX-2 is an inducible enzyme, originally found to be induced by growth factors and other stimuli (7). Previous studies have demonstrated the relevance of COX-2 in human cancer, including colorectal cancer, cholangiocarcinoma, liver cancer, esophageal carcinoma, gastric cancer and pancreatic cancer (8)(9)(10)(11)(12)(13). Determinants of cell invasion, including cell motility, adhesion to the extracellular matrix and the gelatinolytic activity of metalloproteinase, are also modulated in COX-2-positive pancreatic cancer cells (14).…”