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  • The clinical impact of our findings is also supported by

    2024-05-17

    The clinical impact of our findings is also supported by our earlier report that the level of 12-LOX expression was correlated with the tumor stage and grade [17], [52] and that overall, 38% of patients demonstrated elevated levels of 12-LOX in prostate cancer tissue compared with their matching normal tissues. Thus, increased 12-LOX levels might be important in determining the radioresistance in a large sub-population of prostate cancer patients. It is interesting to note that increased levels of free and esterified 12(S)-HETE were detected in cleanup workers from the Chernobyl accident who were exposed to radiation compared to unexposed individuals, indicating an increased accumulation of 12(S)-HETE in irradiated persons [53]. In vitro, we have shown that low-dose γ radiation stimulates 12-LOX activity and biosynthesis of 12(S)-HETE [54]. An exposure to 0.5Gy γ-radiations caused a significant increase in biosynthesis of 12(S)-HETE in B16 melanoma cells as early as 5min. The increased 12(S)-HETE formation led to an enhanced adhesion of B16 melanoma cells to fibronectin in vitro and metastasis in vivo[54]. The results suggest that low-dose radiation, at levels comparable to those used in fractionated or hyper-fractionated radiotherapy, caused a rapid increase in 12-LOX metabolism of arachidonic dgat inhibitor [54]. Taken together, these data emphasize the importance of 12-LOX metabolic activity in cellular response to radiation therapy. The molecular mechanisms regulated by 12-LOX influencing the radiosensitivity of human prostate cancer cells involved the Bcl2/Bax apoptotic pathway. Interestingly, an earlier report emphasized the role of the Bcl-2/Bax ratio as a predictive marker for therapeutic response to radiotherapy in patients with prostate cancer [45]. It would be interesting to explore the selective targeting of this pathway by the use of other apoptosis inducers in combination of 12-LOX inhibition.
    Conflict of Interest
    Acknowledgements
    Introduction There is compelling evidence for an anti-inflammatory effect of 12- and 15-lipoxygenases through the generation of lipid mediators involved in the resolution of inflammation [1]. On the other hand, there is compelling evidence for a pro-atherosclerotic effect through the formation of oxLDL which accelerates foam cell formation and through its role in signalling of angiotensin II mediated mechanisms and vascular smooth muscle cell proliferation [1]. Hence, the 12/15-lipoxygenases seem to be two-faced enzymes with an anti-inflammatory effect through lipid mediator production, and a pro-inflammatory and atherogenic effect through oxLDL formation and participation in signalling pathways [1]. Animal models of atherosclerosis did not solve the question of whether the 12/15-lipoxygenase activity is pro- or anti-atherogenic because different animal models showed contrasting results [2], [3], [4], [5], [6], [7]. Monocyte specific 15-lipoxygenase expression in transgenic rabbits reduced atherosclerosis and supported the anti-inflammatory role of the 15-lipoxygenase [2], [3]. Similarly, an extensive mouse study applying several overexpressing and knockout mouse lines showed an atheroprotective effect of the 15-lipoxygenase under a normal diet [7]. However, conditional macrophage-specific and general disruption of the mouse homolog 12-lipoxygenase gene reduced atherosclerosis [4], [5], while overexpression of human 15-lipoxygenase in vascular endothelium enhanced atherosclerosis in other mouse strains on a cholesterol rich diet [6]. The discrepancies between the different animal models have been explained by the different positional selectivities of the mammalian 12- and 15-lipoxygenase iso-enzymes which oxidize arachidonic acid at the carbon atoms 12 and 15 and which have different expression patterns, and by the composition of the food used in these animal studies [1], [8]. To investigate the role of the 12/15-lipoxygenases in human atherosclerosis, genetic studies have been carried out which investigated the association of the human ALOX15 gene with coronary artery disease and myocardial infarction [9], [10], [11]. Although there is currently more support for a neutral or an atheroprotective role of ALOX15 than for the contrary, these human genetic studies did not consistently show an association of functional variants in ALOX15 with clinical end points of atherosclerosis [12]. The lack of consistent associations may be explained by the lack of power of the studies due to the low frequency of the two functional polymorphisms [12]. However, another explanation may be redundancy for the 12/15-lipoxygenase activity in human macrophages. Recently a second 15-lipoxygenase isoform, ALOX15B, was detected in human atherosclerotic plaques [13], [14]. Immunohistochemical analyses showed abundant ALOX15B expression in macrophage-rich areas of carotid lesions, and lipidomic analyses demonstrated the presence of typical ALOX15B products in plaque tissue [15].