Introduction Lipoxygenases LOXs are key enzymes that
Lipoxygenases (LOXs) are key enzymes that catalyze the polyunsaturated fatty acids (PUFAs) such as arachidic histamine receptor antagonist (AA), linoleic acid (LA) and others unsaturated fatty acids (Brash, 1999). LOXs are expressed in immune, neural, epithelial, tumor cells and other cells (Claesson, 2009). By converting the PUFAs into bioactive metabolites, the enzymes can affect the cell structure, metabolism and signal transduction (Kuhn et al., 2015). LOXs can be found in both animals and plants. Humans have six ALOX genes while the mouse has seven different ALOX genes. LOXs are named based on the numbered carbon where the LOXs oxygenated their PUFA's substrates, for example, 5-LOX. (Mashima and Okuyama, 2015). The activation of LOX enzymes requires either molecular oxygen or lipid hydroperoxides to activate the inactive ferrous form to an active ferric form (Acosta et al., 2009). Moreover, its activation is also regulated by the N-terminal beta-barrel region of polypeptides, where this region has a similar amino acid sequence to the C2-like domain; therefore, Ca2+-mediated activation via interaction with the plasma membrane has been proposed (Werz, 2007). Activation of LOX enzymes displays different physiological functions, including inflammation, erythropoiesis, epidermal differentiation and skin development, cell proliferation and carcinogenesis, tumorigenesis and so on (Haeggstrom and Funk, 2011).
12/15-LOX is a member of LOXs family which is widely distributed in different organizations. 12-LOX can be divided into three types, platelet-type 12-lipoxygenase (p12LOX), leukocyte-type 12-lipoxygenase (l12LOX) and epidermis-type 12-lipoxygenase (e12LOX) (Kuhn and Thiele, 1999). l12LOX deriving from rats, mouse, cattle and pigs is highly homologous to human 15-LOX-1 since both enzymes catalyze AA to produce 12-hydroxy dioctatetraenoic acid (12-HETE) and 15-hydroxy eicosatetraenoic acid (15-HETE) (Berger et al., 1998). That's how 12/15-LOX get named and its' metabolites have stereoisomer nomenclature S and R. The lipid metabolites produced by 12/15-LOX enzymes reacting with PUFAs are involved in a variety of diseases including metabolic, vascular and neurological diseases (Spiteller, 2003).
Recent studies have shown that 12/15-LOX and its metabolites participate in multiple cell death including apoptosis, autophagy and a new cell death program named ferroptosis which is characterized by condensed mitochondrial membrane densities, reduction or vanishing of mitochondria crista, and outerao mitochondrial membrane rupture (Dixon et al., 2012a). Moreover, it is newly reported that 12/15-LOX plays an important role in autophagy and ferroptosis is newly reported. Interestingly, at the beginning, it's thought that ferroptosis is genetically, morphologically, biochemically distinct from apoptosis, necrosis, autophagy and other types of cell death (Dixon et al., 2012b). However, later researches have shown that ferroptosis is associated with autophagy and its relationship needs to be further investigated (Gao et al., 2016; Hamai and Mehrpour, 2017; Hou et al., 2016). It is of great significance to clarify the specific role of 12/15-LOX in different types of cell death since it helps to explain the dual role of 12/15-LOX in different cells and animal models. And it helps to elucidate its role as a potential therapeutic target in disease treatment.
The role of 12/15-LOX plays in apoptosis Apoptosis is a type of programmed cell death which was first proposed by Kerr in 1972 (Kerr et al., 1972). It has been reported that a variety of disease are related to apoptosis including cancer, neurodegenerative disorders, autoimmune disease, virus infective disease and so on (Geisbert et al., 2000; Kuang et al., 2009; Mountz et al., 1994; Zeng et al., 2016; Zhong et al., 2016). In neuron cells, 12/15-LOX participated in apoptosis is mediated by AIF (apoptosis inducing factor) signal pathway which is implicated in caspase-independent forms of apoptosis. Glutathione peroxidase (GPX) which was later confirmed as GPX4 interacted with 12/15-LOX to regulate the redox state of the cells (Kuhn and Borchert). GPX4 could regulate 12/15-LOX to prevent the 12S-HPETE to shift to 12S-HETE and the isomerization to hepoxilins. Meanwhile, glutathione (GSH) was a cofactor for GPX4. GSH depletion has been shown to impair GPX4 function (Hangauer et al., 2017). Correspondingly, through inactivation of GPX4 in mice and cells induced 12/15-LOX-derived lipid peroxidation and then triggered AIF-mediated cell death. Since oxidative stress is related to various human diseases, identifying the GPX4/12/15-LOX proapoptotic pathway provides promising targets for future therapies (Seiler et al., 2008). In addition, the glutamate toxicity cell model is the most commonly used model for studying oxidative stress. Studies have shown that 12/15-LOX characterized by sequentially timed aggregation closing to the nucleus accompanied with mitochondrial AIF translocating to the endoplasmic reticulum and nuclear in excessive glutamate induced cell death in HT22 cell line. While in vivo study, a mouse model of transient focal ischemia was used to investigate the underlying relationship between the expression of 12/15-LOX and AIF in ischemic brain. They found in periinfarct area 12/15-LOX and AIF provide a coordinate upregulation (Pallast et al., 2010). In some cell and animal models which caused apoptosis, through regulating the expression of 12/15-LOX by long noncoding RNA and miRNA contributed to the pathological process. In vivo oxygen-glucose deprivation (MCAO) mice model and in vitro oxygen-glucose deprivation (OGD)-cultured neuronal cell line, it's implicated that the expression of the long noncoding RNA MEG3 and 12/15-LOX were increased and the expression of miR-181b was decreased. This indicated that miR-181b through binding to 3′-UTR of 12/15-LOX negatively regulated 12/15-LOX expression to mediate hypoxia-induced apoptosis (Liu et al., 2016). Moreover, the metabolites of 12/15-LOX through activating its' downstream signal pathway participate in apoptosis. Study has shown that in colorectal cancer cell the 13-S-HODE, the metabolite of 15-LOX may be involved in cell development using the Nonsteroidal anti-inflammatory drugs (NASIDs) which altered the production of the metabolites of linoleic and arachidonic acids though modulating COXs and LOXs to induce growth inhibition. However, results showed that NSAIDs could only up-regulate 15-LOX-1 expression in colon cancer cells. By binding to and activation of PPAR-γ, 13-S-HODE may be involved in the signal-transduction pathway of apoptosis (Shureiqi, Chen, Lee et al.). The similar study was also found in colon cancer cells (Shureiqi, Chen, Lotan et al. In a cultured cardiac myocytes apoptosis cell model treated with stimulated ischemia/reperfusion, baicalein, a specific 12/15-LOX inhibitor significantly inhibited cardiomyocyte apoptosis through activation of ERK1/2 and AKT pathways and inhibition of activation of p38 MAPK, JNK1/2, and NF-ΚB/p65 pathways (Song et al., 2014) (Fig. 1).