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  • and LO are members of the lipoxygenase family

    2023-01-21

    5- and 12/15-LO are members of the lipoxygenase family that convert arachidonic MLN 8237 into lipid mediators such as leukotriene B4 (LTB) and 12()-hydroxyeicosatetraenoic acid (HETE) and 15()-HETE, respectively. Evidence from several in vitro and in vivo studies has shown that activation of the 5- and 12/15-LO pathways is important in inflammation and, by extension, in inflammatory diseases , , , , , . Moreover, the activation of these pathways has been linked to increases in intracellular oxidative stress , . In rodent models in which genes for 5- and 12/15-LO were either disrupted or overexpressed and using inhibitors specific for the pathways, the 5- and 12/15-LO pathways have been implicated in a number of pathological conditions including heart failure, atherosclerosis, type 2 diabetes, diabetic peripheral neuropathy, and neurodegenerative diseases such as Alzheimer disease and f-ALS , , , , , , , , , , , . In addition, the 12/15-LO pathway metabolite 15()-HETE has been shown to increase proteolytic degradation in cultured myotubes by activating the ubiquitin–proteasome system (UPS), suggesting that activation of the 12/15-LO pathway may potentially play a role in skeletal muscle atrophy . However, no such evidence exists in vivo. Moreover, the role of the 5-LO pathway in skeletal muscle biology also remains unknown.
    Introduction Arachidonic acid is metabolized by cyclooxygenases (COX) and lipoxygenases (LOX) into various bioactive lipids which were shown to regulate cell survival, cell cycle control, invasion and the angiogenic phenotype [1]. The mammalian LOX family contains a number of lipid peroxidizing enzymes, which are distinguished by their regional specificity of arachidonic acid oxygenation. Accordingly 5-, 8-, 12-, and 15-LOX isoforms are known, which produce 5(S)-, 8(S)-, 12(S)- and 15(S)-hydroxyeicosatetraenoic acid (HETE) metabolites respectively [2]. 12-LOX has two isoforms, the platelet- and the leukocyte-types sharing 65% DNA homology [3], [4]. In prostate cancer a number of studies outlined the pattern of changes in the expression of AA-metabolizing enzymes. Based on preclinical and clinicopathological studies it is evident that in prostate cancer COX-2, TxS, platelet-type 12-LOX and 15-LO1 (leukocyte-type 12-LOX) are upregulated, while the 15-LOX2 is downregulated, resulting in a characteristic pattern of AA metabolites rich in PGE2, TX, 12-S-HETE, 15-S-HETE and 13-S-HODE [1]. It is interesting, that the ectopic expression of 12-lipoxygenases can be considered as the manifestation of stem cell characteristrics since platelet- or leukocyte-type 12-LOX (15-LO1) are constitutively expressed in bone marrow progenitors [5]. Previous data indicated that 12-S-HETE activates antiapoptotic-, motility- and angiogenic signaling cascades [6], [7], [8]. 12-S-HETE also regulates gene expression including VEGF [8]. 12-LOX levels positively correlated with the stage and grade of prostate cancer [9]. Overexpression of 12-LOX also enhances tumor growth through the induction of angiogenesis [10]. Inhibition of 12-LOX activity with specific inhibitors induced apoptosis and decreased the metastatic potential of DU-145 prostate cancer cells in a lung colonization assay [11]. As screening methods for prostate cancer improve, more patients with localized disease are diagnosed. The curative treatment choice of localized prostate cancer can be both surgery and radiotherapy [12]. Recently, due to patients’ preference, the lower morbidity and the comparable result achieved with radical radiotherapy, the number of prostate radiotherapy treatments both with external irradiation and brachytherapy is increasing [13]. However, radiosensitivity of prostate cancer is variable due to mostly unknown factors among which the geno- and phenotype of the tumor must be important [14]. Therefore, potentiation of the effect of radiotherapy may have clinical relevance in this tumor type as well. Since signaling pathways involving 12-LOX play an important role in the progression of various cancers including prostate cancer [1], we have postulated that 12-LOX derived bioactive lipids may modulate the cytotoxic effect of ionizing radiation as well.