title: 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 E2catabolism 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: Department of Translational Medicine, Division of Cell and Experimental Pathology, Skåne University Hospital Malmö, Lund University, Sweden.
authors: Lubna M
authors: LM
authors: Mehdawi
authors: Department of Translational Medicine, Division of Cell and Experimental Pathology, Skåne University Hospital Malmö, Lund University, Sweden.
authors: Chandra Prakash
authors: CP
authors: Prasad
authors: Department of Translational Medicine, Division of Pathology, Skåne University Hospital Malmö, Lund University, Sweden.
authors: Roy
authors: R
authors: Ehrnström
authors: Department of Translational Medicine, Division of Cell and Experimental Pathology, Skåne University Hospital Malmö, Lund University, Sweden.
authors: Tommy
authors: T
authors: Andersson
authors: Department of Translational Medicine, Division of Cell and Experimental Pathology, Skåne University Hospital Malmö, Lund University, Sweden. Electronic address: anita.sjolander@med.lu.se.
authors: Anita
authors: A
authors: Sjölander
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D018938:Caco-2 Cells; D002454:Cell Differentiation / Q000235:genetics*; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D019073:HT29 Cells; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000235:genetics* / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008819:Mice, Nude; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction; D015854:Up-Regulation / Q000235:genetics*; D000071818:Wnt-5a Protein / Q000378:metabolism*
chemical_list: C542624:Foxy-5 peptide; D009842:Oligopeptides; C085389:WNT5A protein, human; D000071818:Wnt-5a Protein; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase
keywords: 15-PGDH; Colon cancer; JNK; WNT-5A; β-Catenin