Evaluation of Cysteinyl Leukotriene Signaling As a Therapeutic Target for Colorectal Cancer

Overview

Journal Front Cell Dev Biol

Specialty Cell Biology

Date 2016 Oct 7

PMID 27709113

Citations 21

Authors

Lorraine Burke

Clare T Butler

Adrian Murphy

Bruce Moran

William M Gallagher

Jacintha OSullivan

Breandan N Kennedy

Affiliations

Soon will be listed here.

Abstract

Colorectal cancer is the third most common cancer worldwide and is associated with significant morbidity and mortality. Current pharmacotherapy options include cytotoxic chemotherapy, anti-VEGF, and anti-EGFR targeting drugs, but these are limited by toxic side effects, limited responses and ultimately resistance. Cysteinyl leukotriene (CysLT) signaling regulates intestinal homeostasis with mounting evidence suggesting that CysLT signaling also plays a role in the pathogenesis of colorectal cancer. Therefore, CysLT signaling represents a novel target for this malignancy. This review evaluates reported links between CysLT signaling and established hallmarks of cancer in addition to its pharmacological potential as a new therapeutic target.

Citing Articles

Cysteinyl leukotriene receptor 1 modulates retinal immune cells, vascularity and proteolytic activity in aged mice.

Koller A, Preishuber-Pflugl J, Mayr D, Brunner S, Ladek A, Runge C Aging (Albany NY). 2025; 17(2):308-328.

PMID: 39891615 PMC: 11892928. DOI: 10.18632/aging.206193.

Histamine and TH2 cytokines regulate the biosynthesis of cysteinyl-leukotrienes and expression of their receptors in human mast cells.

Gehlhaar P, Schaper-Gerhardt K, Gutzmer R, Hasler F, Rohn T, Werfel T Inflamm Res. 2025; 74(1):32.

PMID: 39890627 PMC: 11785601. DOI: 10.1007/s00011-024-01974-6.

The tumor promoter cysteinyl leukotriene receptor 1 regulates PD-L1 expression in colon cancer cells via the Wnt/β-catenin signaling axis.

Satapathy S, Ghatak S, Sjolander A Cell Commun Signal. 2023; 21(1):138.

PMID: 37316937 PMC: 10265834. DOI: 10.1186/s12964-023-01157-6.

DNA Methylation and Gene Expression of the Cysteinyl Leukotriene Receptors as a Prognostic and Metastatic Factor for Colorectal Cancer Patients.

Ghatak S, Satapathy S, Sjolander A Int J Mol Sci. 2023; 24(4).

PMID: 36834820 PMC: 9963074. DOI: 10.3390/ijms24043409.

1,4-dihydroxy quininib modulates the secretome of uveal melanoma tumour explants and a marker of oxidative phosphorylation in a metastatic xenograft model.

Slater K, Bosch R, Smith K, Jahangir C, Garcia-Mulero S, Rahman A Front Med (Lausanne). 2023; 9:1036322.

PMID: 36698840 PMC: 9868667. DOI: 10.3389/fmed.2022.1036322.

References

Jupp J, Hillier K, Elliott D, Fine D, Bateman A, Johnson P . Colonic expression of leukotriene-pathway enzymes in inflammatory bowel diseases. Inflamm Bowel Dis. 2007; 13(5):537-46. DOI: 10.1002/ibd.20094. View

Paruchuri S, Hallberg B, Juhas M, Larsson C, Sjolander A . Leukotriene D(4) activates MAPK through a Ras-independent but PKCepsilon-dependent pathway in intestinal epithelial cells. J Cell Sci. 2002; 115(Pt 9):1883-93. DOI: 10.1242/jcs.115.9.1883. View

Savari S, Liu M, Zhang Y, Sime W, Sjolander A . CysLT(1)R antagonists inhibit tumor growth in a xenograft model of colon cancer. PLoS One. 2013; 8(9):e73466. PMC: 3764114. DOI: 10.1371/journal.pone.0073466. View

Bengtsson A, Jonsson G, Magnusson C, Salim T, Axelsson C, Sjolander A . The cysteinyl leukotriene 2 receptor contributes to all-trans retinoic acid-induced differentiation of colon cancer cells. BMC Cancer. 2013; 13:336. PMC: 3710469. DOI: 10.1186/1471-2407-13-336. View

Yuan Y, Fang S, Qian X, Liu L, Xu L, Shi W . Leukotriene D4 stimulates the migration but not proliferation of endothelial cells mediated by the cysteinyl leukotriene cyslt(1) receptor via the extracellular signal-regulated kinase pathway. J Pharmacol Sci. 2009; 109(2):285-92. DOI: 10.1254/jphs.08321fp. View

Tsopanoglou N, Maragoudakis M . Leukotrienes C4 and D4 promote angiogenesis via a receptor-mediated interaction. Eur J Pharmacol. 1994; 258(1-2):151-4. DOI: 10.1016/0014-2999(94)90068-x. View

Sakamoto K, Frank D . CREB in the pathophysiology of cancer: implications for targeting transcription factors for cancer therapy. Clin Cancer Res. 2009; 15(8):2583-7. PMC: 2883446. DOI: 10.1158/1078-0432.CCR-08-1137. View

Paruchuri S, Broom O, Dib K, Sjolander A . The pro-inflammatory mediator leukotriene D4 induces phosphatidylinositol 3-kinase and Rac-dependent migration of intestinal epithelial cells. J Biol Chem. 2005; 280(14):13538-44. DOI: 10.1074/jbc.M409811200. View

Paruchuri S, Sjolander A . Leukotriene D4 mediates survival and proliferation via separate but parallel pathways in the human intestinal epithelial cell line Int 407. J Biol Chem. 2003; 278(46):45577-85. DOI: 10.1074/jbc.M302881200. View

10.

He T, Sparks A, Rago C, Hermeking H, Zawel L, DA COSTA L . Identification of c-MYC as a target of the APC pathway. Science. 1998; 281(5382):1509-12. DOI: 10.1126/science.281.5382.1509. View

11.

Xu L, Zhang L, Liu L, Fang S, Lu Y, Wei E . Involvement of cysteinyl leukotriene receptors in angiogenesis in rat thoracic aortic rings. Pharmazie. 2010; 65(10):750-4. View

12.

Magi S, Takemoto Y, Kobayashi H, Kasamatsu M, Akita T, Tanaka A . 5-Lipoxygenase and cysteinyl leukotriene receptor 1 regulate epidermal growth factor-induced cell migration through Tiam1 upregulation and Rac1 activation. Cancer Sci. 2013; 105(3):290-6. PMC: 4317946. DOI: 10.1111/cas.12340. View

13.

Magnusson C, Mezhybovska M, Lorinc E, Fernebro E, Nilbert M, Sjolander A . Low expression of CysLT1R and high expression of CysLT2R mediate good prognosis in colorectal cancer. Eur J Cancer. 2010; 46(4):826-35. DOI: 10.1016/j.ejca.2009.12.022. View

14.

Henderson Jr W . The role of leukotrienes in inflammation. Ann Intern Med. 1994; 121(9):684-97. DOI: 10.7326/0003-4819-121-9-199411010-00010. View

15.

He W, Miao F, Lin D, Schwandner R, Wang Z, Gao J . Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors. Nature. 2004; 429(6988):188-93. DOI: 10.1038/nature02488. View

16.

Bokemeyer C, Van Cutsem E, Rougier P, Ciardiello F, Heeger S, Schlichting M . Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer. 2012; 48(10):1466-75. DOI: 10.1016/j.ejca.2012.02.057. View

17.

Porreca E, di Febbo C, Di Sciullo A, Angelucci D, Nasuti M, Vitullo P . Cysteinyl leukotriene D4 induced vascular smooth muscle cell proliferation: a possible role in myointimal hyperplasia. Thromb Haemost. 1996; 76(1):99-104. View

18.

Hirohashi S . Inactivation of the E-cadherin-mediated cell adhesion system in human cancers. Am J Pathol. 1998; 153(2):333-9. PMC: 1852964. DOI: 10.1016/S0002-9440(10)65575-7. View

19.

Wang G, Yang Z, Zhang K . Endoplasmic reticulum stress response in cancer: molecular mechanism and therapeutic potential. Am J Transl Res. 2010; 2(1):65-74. PMC: 2826823. View

20.

Kanaoka Y, Boyce J . Cysteinyl leukotrienes and their receptors: cellular distribution and function in immune and inflammatory responses. J Immunol. 2004; 173(3):1503-10. DOI: 10.4049/jimmunol.173.3.1503. View