The cysteinyl leukotriene 2 receptor contributes to all-transretinoic acid-induced differentiation of colon cancer cellsReportar como inadecuado

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BMC Cancer

, 13:336

Cell and molecular biology


BackgroundCysteinyl leukotrienes CysLTs are potent pro-inflammatory mediators that are increased in samples from patients with inflammatory bowel diseases IBDs. Individuals with IBDs have enhanced susceptibility to colon carcinogenesis. In colorectal cancer, the balance between the pro-mitogenic cysteinyl leukotriene 1 receptor CysLT1R and the differentiation-promoting cysteinyl leukotriene 2 receptor CysLT2R is lost. Further, our previous data indicate that patients with high CysLT1R and low CysLT2R expression have a poor prognosis. In this study, we examined whether the balance between CysLT1R and CysLT2R could be restored by treatment with the cancer chemopreventive agent all-trans retinoic acid ATRA.

MethodsTo determine the effect of ATRA on CysLT2R promoter activation, mRNA level, and protein level, we performed luciferase gene reporter assays, real-time polymerase chain reactions, and Western blots in colon cancer cell lines under various conditions.

ResultsATRA treatment induces CysLT2R mRNA and protein expression without affecting CysLT1R levels. Experiments using siRNA and mutant cell lines indicate that the up-regulation is retinoic acid receptor RAR dependent. Interestingly, ATRA also up-regulates mRNA expression of leukotriene C4 synthase, the enzyme responsible for the production of the ligand for CysLT2R. Importantly, ATRA-induced differentiation of colorectal cancer cells as shown by increased expression of MUC-2 and production of alkaline phosphatase, both of which could be reduced by a CysLT2R-specific inhibitor.

ConclusionsThis study identifies a novel mechanism of action for ATRA in colorectal cancer cell differentiation and demonstrates that retinoids can have anti-tumorigenic effects through their action on the cysteinyl leukotriene pathway.

KeywordsAll-trans retinoic acid ATRA CysLT2R Leukotriene Leukotriene receptor Colon cancer Inflammation Electronic supplementary materialThe online version of this article doi:10.1186-1471-2407-13-336 contains supplementary material, which is available to authorized users.

Astrid M Bengtsson, Gunilla Jönsson contributed equally to this work.

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Autor: Astrid M Bengtsson - Gunilla Jönsson - Cecilia Magnusson - Tavga Salim - Cecilia Axelsson - Anita Sjölander


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