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Open Access Research article

The cysteinyl leukotriene 2 receptor contributes to all-trans retinoic acid-induced differentiation of colon cancer cells

Astrid M Bengtsson2, Gunilla Jönsson1, Cecilia Magnusson1, Tavga Salim1, Cecilia Axelsson1 and Anita Sjölander1*

Author Affiliations

1 Department of Laboratory Medicine, Cell and Experimental Pathology, Lund University, Malmö University Hospital, SE-205 02, Malmö, Sweden

2 Present name and address, Astrid Friborg at Berries by Astrid, Stockholm, Sweden

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BMC Cancer 2013, 13:336  doi:10.1186/1471-2407-13-336

Published: 8 July 2013

Abstract

Background

Cysteinyl 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).

Methods

To 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.

Results

ATRA 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.

Conclusions

This 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.

Keywords:
All-trans retinoic acid (ATRA); CysLT2R; Leukotriene; Leukotriene receptor; Colon cancer; Inflammation