Mesalazine initiates an anti-oncogenic β-catenin / MUCDHL negative feed-back loop in colon cancer cells by cell-specific mechanisms

• Published in: Biomedicine & pharmacotherapy Vol. 146; p. 112543
• Main Authors: Bersuder, Emilie, Terciolo, Chloe, Lechevrel, Mathilde, Martin, Elisabeth, Quesnelle, Celine, Freund, Jean-Noel, Reimund, Jean-Marie, Gross, Isabelle
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01.02.2022; Elsevier
• Subjects: 5-aminosalicylic acid; Adhesion; beta Catenin - metabolism; Cadherin Related Proteins; Cadherins - genetics; Cadherins - metabolism; Cancer; CDHR5; Colonic Neoplasms - drug therapy; Colonic Neoplasms - genetics; Colonic Neoplasms - metabolism; Colorectal neoplasm; Colorectal Neoplasms - genetics; Humans; Life Sciences; Mesalamine - pharmacology; Ulcerative Colitis; WNT pathway; Wnt Signaling Pathway; Ab; WNT pathway; IMAC; HRP; 5-aminosalicylic acid; IBD; Adhesion; UC; Cdhr; 5-ASAs; CRC; Ulcerative Colitis; Colorectal neoplasm; CDHR5
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2021.112543

Chronic inflammation associated with intestinal architecture and barrier disruption puts patients with inflammatory bowel disease (IBD) at increased risk of developing colorectal cancer (CRC). Widely used to reduce flares of intestinal inflammation, 5-aminosalicylic acid derivatives (5-ASAs) such as mesalazine appear to also exert more direct mucosal healing and chemopreventive activities against CRC. The mechanisms underlying these activities are poorly understood and may involve the up-regulation of the cadherin-related gene MUCDHL (CDHR5). This atypical cadherin is emerging as a new actor of intestinal homeostasis and opposes colon tumorigenesis. Here, we showed that mesalazine increase mRNA levels of MUCDHL and of other genes involved in the intestinal barrier function in most intestinal cell lines. In addition, using gain / loss of function experiments (agonists, plasmid or siRNAs transfections), luciferase reporter genes and chromatin immunoprecipitation, we thoroughly investigated the molecular mechanisms triggered by mesalazine that lead to the up-regulation of MUCDHL expression. We found that basal transcription of MUCDHL in different CRC cell lines is regulated positively by CDX2 and negatively by β-catenin through a negative feed-back loop. However, mesalazine-stimulation of MUCDHL transcription is controlled by cell-specific mechanisms, involving either enhanced activation of CDX2 and PPAR-γ or repression of the β-catenin inhibitory effect. This work highlights the importance of the cellular and molecular context in the activity of mesalazine and suggests that its efficacy against CRC depends on the genetic alterations of transformed cells. [Display omitted] •Mesalazine stimulates the expression of genes of the intestinal brush border.•MUCDHL is regulated by β-catenin, CDX2 and PPAR-γ.•Activity of Mesalazine in colorectal cancer cells depends on genetic alterations.