Cysteinyl leukotrienes and their receptors: bridging inflammation and colorectal cancer

Abstract

Long-standing inflammation has emerged as a hallmark of neoplastic transformation of epithelial cells and may be a limiting factor of successful conventional tumor therapies. A complex milieu composed of distinct stromal and immune cells, soluble factors and inflammatory mediators plays a crucial role in supporting and promoting various types of cancers. An augmented inflammatory response can predispose a patient to colorectal cancer (CRC). Common risk factors associated with CRC development include diet and lifestyle, altered intestinal microbiota and commensals, and chronic inflammatory bowel diseases. Cysteinyl leukotrienes are potent inflammatory metabolites synthesized from arachidonic acid and have a broad range of functions involved in the etiology of various pathologies. This review discusses the important role of cysteinyl leukotriene signaling in linking inflammation and CRC.

Keywords: Colorectal cancer; CysLT1R; CysLT2R; Cysteinyl leukotrienes; Eicosanoids; Inflammation.

Figure 1

Overview of arachidonic acid metabolism. Arachidonic acid (AA) is a polyunsaturated fatty acid found in the phospholipids of cell membranes. AA is mobilized into the cytoplasm mostly by the activation of calcium-dependent cytosolic phospholipase A₂ (cPLA₂). Free AA in the cytosol can be enzymatically metabolized to eicosanoids through three major pathways: the cytochrome P450, cyclooxygenase (COX) and/or 5-lipoxygenase (5-LOX) pathways. In the P450 pathway, AA is metabolized to epoxyeicosatrienoic acids (EETs), hydroxyeicosatetraenoic acids (HETEs) and hydroperoxyeicosatetraenoic acids (HPETEs). In the COX pathway, AA is enzymatically converted to the intermediate prostaglandin H₂ (PGH₂), which is then sequentially metabolized to prostanoids, including prostaglandins (PGs), such as PGE₂, PGF₂, PGD₂ and PGI₂, and thromboxanes (TXs) such as TXA₂ by specific prostaglandin and thromboxane synthases. In the LOX pathway, AA is metabolized by 12- and 15-LOX to 8-, 12- and 15-HPETE or by 5-LOX and 5-lipoxygenase activating protein (FLAP) to intermediary 5-HPETE. 5-HPETE is further processed to form leukotrienes (LTs), the first of which is the unstable leukotriene A₄ (LTA₄). LTA₄ is subsequently converted to leukotriene B₄ (LTB₄) by LTA₄ hydrolase or together with glutathione to leukotriene C₄ (LTC₄) by LTC₄ synthase and glutathione-S-transferase. LTC₄ is converted by ubiquitous enzymes to form leukotriene D₄ (LTD₄) and leukotriene E₄ (LTE₄). The members of the multidrug resistance-associated protein (MRP) family are efflux transporters for both PGs and LTs. The cysteinyl leukotrienes (CysLTs) LTC₄, LTD₄ and LTE₄ act via G protein-coupled receptors CysLT₁R and CysLT₂R at the cell surface and induce different signaling mechanisms.

Figure 2

Signaling pathways of LTD₄ and CysLT₁R. Upon stimulation with LTD₄, various downstream signaling pathways become activated. LTD₄ induces cell membrane ruffles through phosphoinositide 3-kinase (PI3K) signaling, which in turn stimulates protein kinase Akt/PKB and the small GTPases Rho and Rac. Akt/PKB can inhibit glycogen synthase kinase-3 β (GSK-3β), which comprises the destruction complex for cytosolic β-catenin together with Axin and adenomatous polyposis coli (APC). Inhibition of the destruction complex leads to the accumulation of β-catenin in the cytosol and translocation to the nucleus. In the nucleus, β-catenin interacts primarily with members of the T-cell factor/lymphoid enhancer factor (TCF/LEF) family of transcription factors to activate target genes, leading to the expression of various proteins, such as cyclin D1, COX-2 and c-Myc, which contribute to diverse cellular processes, including proliferation and migration. LTD₄-CysLT₁R signaling also regulates cell proliferation via mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (Erk) pathways. LTD₄-CysLT₁R in turn activates phospholipase C (PLC), Raf-1 and mitogen-activated protein kinase kinase (MEK-1/2). This activation leads to the translocation of p-Erk from the cytosol to the nucleus and interaction with p90^RSK, which can activate various transcription factors. Conversely, LTD₄-CysLT₁R mediates survival through protein kinase Cα (PKCα) and the transcription factor cAMP response element-binding protein (CREB). β-cat: β-catenin.