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Mesalazine Regulates DUSP1, DUSP4, and DUSP5 Expression in Colorectal Cancer: In Vitro and Bioinformatic Evidence
Marcel Madej1,2, Ilona Nowak1,2, Barbara Strzałka-Mrozik1
1Department of Molecular Biology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, 40-055 Katowice, Poland.
Abstract:
Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality worldwide, with its development closely linked to dysregulation of mitogen-activated protein kinase (MAPK) signaling pathways. Background: Dual-specificity phosphatases (DUSPs), as key regulators of MAPKs, play a crucial role in maintaining the balance between proliferation and apoptosis. Methods: In this study, we investigated the effect of mesalazine (MES) on the expression and activity of selected DUSP family members in normal colon epithelial cells (CCD-841CoN) and colorectal cancer cells (DLD-1). Results: Microarray analysis identified 24 transcripts with altered expression upon mesalazine treatment. The number of significantly regulated genes decreased with increasing fold-change (FC) thresholds, from 20 genes (FC > 1.1) to 13 (FC > 1.5) and 5 (FC > 2.0), all with p < 0.001. Among the DUSP genes, DUSP4 and DUSP5 showed the most pronounced and cell-type-dependent modulation. Mesalazine upregulated DUSP4 and DUSP5 expression in DLD-1 cells (p < 0.001), while reducing their expression in normal CCD-841CoN cells. ELISA confirmed a 1.56-fold increase in DUSP5 protein concentration in mesalazine-treated cancer cells compared with controls (p < 0.001). Conclusions: These findings suggest that mesalazine differentially modulates DUSP gene expression in normal and malignant colon epithelial cells, potentially contributing to its antiproliferative and pro-apoptotic effects through the regulation of MAPK signaling. These results provide new insights into the molecular mechanisms underlying the anticancer effects of mesalazine in colorectal cancer.
Insights
Mesalazine differentially affects dual-specificity phosphatase (DUSP) gene expression in colon cells. This suggests mesalazine may combat colorectal cancer by regulating mitogen-activated protein kinase (MAPK) signaling.
Area of Science:
- Molecular Biology
- Cancer Research
- Pharmacology
Background:
- Colorectal cancer (CRC) is a leading cause of cancer mortality globally.
- Dysregulation of mitogen-activated protein kinase (MAPK) signaling pathways is implicated in CRC development.
- Dual-specificity phosphatases (DUSPs) are key regulators of MAPKs, balancing cell proliferation and apoptosis.
Purpose of the Study:
- To investigate the impact of mesalazine (MES) on DUSP family members in normal and colorectal cancer cells.
- To elucidate the molecular mechanisms of mesalazine's potential anticancer effects in CRC.
Main Methods:
- Microarray analysis to assess gene expression changes in response to mesalazine.
- Enzyme-linked immunosorbent assay (ELISA) to quantify protein level changes.
- Experiments conducted on normal colon epithelial cells (CCD-841CoN) and colorectal cancer cells (DLD-1).
Main Results:
- Mesalazine treatment altered the expression of 24 transcripts in colon cells.
- DUSP4 and DUSP5 expression was upregulated in DLD-1 cancer cells but downregulated in CCD-841CoN normal cells.
- ELISA confirmed a significant increase in DUSP5 protein in mesalazine-treated cancer cells.
Conclusions:
- Mesalazine exhibits differential modulation of DUSP gene expression between normal and malignant colon cells.
- These findings suggest a mechanism for mesalazine's antiproliferative and pro-apoptotic effects via MAPK pathway regulation.
- The study provides novel insights into mesalazine's molecular action against colorectal cancer.
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