Non-canonical WNT5A signaling up-regulates the expression of the tumor suppressor 15-PGDH and induces differentiation of colon cancer cells.

Abstract

The tumor suppressor 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is the key enzyme in prostaglandin E2 catabolism and is down-regulated in colorectal cancer (CRC) tissue. Canonical Wnt signaling is frequently elevated in colon cancers and has been shown to down-regulate 15-PGDH expression. Therefore, we have in the current study investigated if the non-canonical ligand WNT5A relates to increased expression of 15-PGDH in colon cancer cells. In the same cohort of patients, we demonstrated a parallel and significant loss of 15-PGDH and WNT5A protein expression in CRC tissues compared with matched normal colon tissues. Furthermore, patients with low 15-PGDH/WNT5A expression in their tumors showed reduced survival compared with patients with high 15-PGDH/WNT5A expression. To investigate if WNT5A signaling directly affects 15-PGDH expression, we performed in vitro analyses of colon cancer cells (HT-29 and Caco-2). Both cell lines, when treated with recombinant WNT5A (rWNT5A) or Foxy-5, a WNT5A-mimicking peptide, responded by increasing their expression of 15-PGDH mRNA and protein. Our investigations showed that rWNT5A and Foxy-5 induced this increased expression of 15-PGDH through reduced β-catenin signaling as well as increased JNK/AP-1 signaling in colon cancer cells. WNT5A signaling also induced increased 15-PGDH expression in a breast cancer cell line both in vitro and in vivo. In agreement, WNT5A signaling also increased the expression of the differentiation markers sucrose-isomaltase and mucin-2 in colon cancer cells. Our results show that WNT5A signaling regulates 15-PGDH expression, thus uncovering a novel mechanism by which WNT5A acts as a tumor suppressor and suggests that increased 15-PGDH expression could be used as an indicator of a positive response to Foxy-5 in patients treated with this WNT5A agonist.

• Authors: Lubna M Mehdawi, Chandra Prakash Prasad, Roy Ehrnström, Tommy Andersson, Anita Sjölander
• Journal: Molecular oncology (Mol Oncol) Vol. 10 Issue 9 Pg. 1415-1429 (11 2016) ISSN: 1878-0261 [Electronic] United States
• PMID: 27522468 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Chemical References

• Foxy-5 peptide
• Oligopeptides
• WNT5A protein, human
• Wnt-5a Protein
• Hydroxyprostaglandin Dehydrogenases
• 15-hydroxyprostaglandin dehydrogenase

Topics

• Animals
• Breast Neoplasms (genetics, pathology)
• Caco-2 Cells
• Cell Differentiation (genetics)
• Colonic Neoplasms (drug therapy, genetics, pathology)
• Female
• Gene Expression Regulation, Neoplastic
• HT29 Cells
• Humans
• Hydroxyprostaglandin Dehydrogenases (genetics, metabolism)
• Kaplan-Meier Estimate
• Mice, Nude
• Oligopeptides (pharmacology, therapeutic use)
• Signal Transduction
• Up-Regulation (genetics)
• Wnt-5a Protein (metabolism)