Cysteinyl leukotrienes and their receptors: Bridging inflammation and colorectal cancer

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.