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

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.