Introduction Chronic inflammation is increasingly known as

Introduction Chronic inflammation is increasingly known as one of the most critical etiological factors in gastrointestinal (GI) cancers (Lee et al., 2016; Wang and Cho, 2015). Overexpression of 5-lipoxygenase (5-LOX), 5-LOX-activating protein (FLAP), as well as other leukotriene (LT) biosynthetic enzymes have been reported in many malignant SR 1664 mg of the GI tract including the colon, rectum, esophagus, and pancreas (Chen et al., 2004; Li et al., 2005; Melstrom et al., 2008; Wasilewicz et al., 2010). There are several pieces of evidence suggesting that 5-LOX triggers the progression and initiation of GI malignancies (Moore and Pidgeon, 2017; Ringleb et al., 2018). For example, a study by Hoque et al. (Hoque et al., 2005a, 2005b) revealed that 5-LOX inhibitors in esophageal tumor cell lines, led to a time and dose dependent decrease in cell viability as well as induced apoptosis, which is linked to the 5-LOX expression levels and LTB4 production in these tumor cell lines. Another study by Romano et al. (Romano et al., 2001a, 2001b) showed that an important mechanism of 5-LOX expression on apoptosis and cell proliferation is associated with the modulation of VEGF and the levels of mRNA by 5-LOX in malignant mesothelial cells. Likewise, an inflammation-related colon cancer development model investigation found that the expression of 5-LOX is accompanied by the up-regulation of matrix metalloproteinase (MMP) −2 as well as VEGF expression, which are two most important features of angiogenesis in GI malignancies (Ye et al., 2004). Another study revealed that the inhibition of 5-LOX induces the cell death (apoptosis) in pancreatic cancer (PC) cell lines (Zhou et al., 2015). Cysteinyl LT 1 receptor (CysLT1R) antagonists and 5-LOX inhibitors are known to modulate the LT pathway (Boudreau et al., 2017; Csandl et al., 2016). Overexpression of CysLT1R in various GI cancers suggests that LT might play an essential function in the pathogenesis of these malignancies (Bengtsson et al., 2013; Osman et al., 2017; Ozkan et al., 2010; Sun et al., 2015). In addition, CysLT1R antagonists, montelukast have also been reported to inhibit tumor progression by inducing apoptosis (Tsai et al., 2017, 2016). Increased expression of 5-LOX in various GI cancers indicates that 5-LOX is a possible target for GI cancer (Hoque et al., 2005a, 2005b). Quantitative messenger (transcript) and protein analysis reported that amplified expression of 5-LOX in PC tissues is associated with TNM stage and lymph node metastasis (Zhou et al., 2015). Additionally, 5-LOX inhibitors showed cytotoxic effects independent of 5-LOX activity (Fischer et al., 2010). 5-LOX gene silencing methods and 5-LOX inhibitor trials revealed suppression of tumorigenic Wnt signaling and impaired tumor cell growth (Roos et al., 2016, 2014). Although, the pharmacological drugs targeting 5-LOX have shown antitumorigenic effects on GI cancer, clinical trials using these agents appear to be prone to significant off-target effects. The emphasis of this review is to understand the role of 5-LOX in GI cancers.
5-lipoxygenase Arachidonate 5-LOX or oxygen 5-LOX is a dioxygenase enzyme rich in non-heme iron (Needleman et al., 1986). This dioxygenase enzyme catalyzes LT from arachidonic acid (AA) (Sundaram and Ghosh, 2006). In general, AA is rich in polyunsaturated fatty acids and initiates the progression of many cancers (Cianchi et al., 2006). Cancer progression is also associated with AA metabolites such as eicosanoids that perform as mitogens (Anderson et al., 1998). The initial two steps in LT development are catalyzed by 5-LOX (Steinhilber et al., 2010), and the chemical reaction begins with in the cell production of AA. 5-LOX along with 5-LOX-activating proteins supports the catalysis of AA oxidation into 5(S)-hydroxy-6-trans-8,11,14-cis-eicosatetraenoic acid (5-HETE) (Sundaram and Ghosh, 2006), which is a direct result from the formation of epoxide LTA4 from dehydrated 5-HETE (Peters-Golden, 1998). LTA4 is further processed to form LTB4 or LTC4 either via LTA4 hydrolase enzymes through stereo-selective hydration or via glutathione conjugation catalyzed by LTC4 synthase (Avis et al., 2001). A series of consecutive metabolic reactions such as γ-glutamyltransferase is involved in the conversion of LTC4 to LTD4 and LTE4 (Steele et al., 1999). Activated 5-LOX enzymes translocate into the nucleoplasm where the activating proteins assist in the relocation of phospholipid-derived AA to 5-LOX. The efficient conversion of LTA4 from 5-HETE initiates 5-LOX development (Steinhilber et al., 2010). These oxidized molecules of 5-HETE and LTs induce tumor propagation and sustainability (Nieves and Moreno, 2006) by interacting with the G-protein-coupled transmembrane receptor OXER1 (Ghosh and Myers, 1997). Recent investigations have revealed that growth factors like epidermal growth factors (EGF) as well as neurotensin are involved in tumor progression facilitated by 5-LOX in various cancers (Hassan and Carraway, 2006; Karlage et al., 2010). 5-LOX can facilitate tumorigenesis directly by regulating the tumor cell and/or indirectly via modulating the tumor microenvironment. Studies including the genetic mutations (Baker et al., 2013) and certain inhibitors of 5-LOX (Cuendet and Pezzuto, 2000) (Fig. 1; Table 1) have shown the association of 5-LOX with tumor metastasis. Mutant studies suggested that catalytic activity is necessary for 5-LOX-associated effects on CRC cell line proliferation and metastasis (Baker et al., 2013). A study conducted on CRC patients revealed that 5-HETE, a metabolite of 5-LOX, elevated the VEGF expression levels and thereby initiated angiogenesis (Romano et al., 2001a, 2001b; Ye et al., 2005). Downstream activation of 5-LOX is known to be involved with AKT and ERK, which might play a vital role in advancing angiogenesis in cancer cells (Payne et al., 2007). Amplified 5-LOX as well as MMP activity is associated with the extracellular matrix (ECM) stiffness (Levental et al., 2009) and has induced invasion and metastasis in cancerous cells (Erler et al., 2009; Kirschmann et al., 2002). All of these discoveries reveal that 5-LOX plays an essential function in inducing tumor cell proliferation and metastasis including migration, invasion, adhesion and angiogenesis.