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LOX and cancer

There is a steadily increasing evidence from animal models and clinical observations indicating that LOX and their products may play a role in tumor formation and cancer metastasis [1-4]. Recently the concept has been put forward that LOX activation may be involved in both pro- and antitumorigenic effects [5].

i) procarcinogenic effects:

Many data show a correlation between a high expression of different LOX-isoforms and the development of human and experimental tumors suggesting a procarcinogenic role.
High expression of 5-LOX was found in prostate, lung and other cancer cell lines [6, 7]. 5-LOX is overexpressed in human pancreatic cancer, and 5S-HETE formation or inhibition respectively promote or inhibit the growth of prostate cancer cells [8, 9]. 5-LOX inhibitors can inhibit growth of mouse colon adenocarcinoma cell lines in vitro and in vivo [10].
Overexpression of platelet-type12S-LOX has been found in a variety of tumors including breast, colorectal and prostate cancer [11, 12] and has been shown to be present in a number of prostate, melanoma and other cancer cell lines [13-15]. The degree of 12-LOX overexpression in human prostate cancer correlates with the tumor grade and stage [1]. Forced overexpression of 12-LOX in prostate cancer cells increased angiogenesis and growth of tumors in mice [16]. Inhibition of the 12-LOX pathway in prostate cancer cells has been shown to induce apoptosis [17].
Overexpression of 15-LOX-1 has been reported in human prostate tumors [18], and overexpression correlates with the tumor grade [19]. Other reports show overexpression of 15-LOX-1 in human colorectal tumors [20] and breast carcinoma cells [21]. Suppression of the LOX pathways has been found to inhibit tumor formation in animal models such as the initiation-promotion approach of mouse skin carcinogenesis [4]. Upon tumor induction in mouse skin the LOX isoforms 8S- LOX and platelet-type12S-LOX have been found to be aberrantly overexpressed in papillomas and squamous cell carcinomas, leading to an accumulation of the corresponding metabolites 8S- and 12S-HETE [22, 23]. Both LOX products have been shown to induce chromosomal damage in primary basal mouse keratinocytes [24, 25]. Moreover, targeted overexpression of 8S-LOX in mouse skin strongly increased malignant conversion of papillomas but had no effect on the generation of these benign tumors [26]. In addition, platelet-type 12S-LOX-deficient mice have been shown to be less sensitive for tumor induction according to the initiation-promotion protocol [27].

ii) anticarcinogenic effects:

Downregulation of distinct LOXs in the course of tumor development indicate that these isoforms may cause antitumorigenic rather than protumorigenic. 15-LOX-2 expression has been found to be reduced in prostate cancer and high-grade prostatic intraepithelial neoplasia [28, 29]. 15S-LOX-1 expression was also reduced in human colorectal cancer [30], although this observation was confounded by another report [20].

iii) antagonistic effects of LOX products

12S-HETE and 13S-HODE have been proposed to have opposite effects on tumorigenesis. 12S-HETE is thought to enhance carcinogenesis due to an up-regulation of tumor cell adhesion molecules [31, 32], a stimulation of angiogenesis [12] and of tumor cell spreading [33], and an inhibition of apoptosis [34]. In contrast, 13S-HODE is likely to have antitumorigenic effects due to an induction of apoptosis and cell cycle arrest [30, 35] and an induction of differentiation [36, 37]. Both metabolites exhibit antagonistic effects on experimental tumor induction in mouse skin. Arachidonic acid has been shown to have a protumorigenic activity that is inhibited by linoleic acid. Accordingly, 12S-HETE has been reported to stimulate keratinocyte proliferation and adhesion to fibronectin, and to inhibit terminal differentiation of keratinocytes [38, 39] whereas 13S-HODE was found to reverse epidermal hyperproliferation in the skin of guinea pigs [40], to counteract the inhibition of terminal differentiation by 12S-HETE, and to prevent keratinocyte adhesion to fibronectin [41].
Transgenic mice overexpressing epidermis-type 12S-LOX in skin at high level showed increased tumor response which was parralleled by strong accumulation of the archidonic acid metabolite 12-HETE, whereas low transgene expression resulted in a reduced tumor response paralleled by an upregulation of the leukocyte-type 12S-LOX and an accumulation of the linoleic acid product 13-HODE indicating a complex interaction between different LOX isoforms and opposite roles of arachidonic acid and linoleic acid metabolites in the modulation of epidermal carcinogenesis [42].
In prostate cancer cells 13-HODE, a 15-LOX-1 metabolite up-regulates MAPK and Akt pathways, whereas15-HETE, a 15-LOX-2 metabolite downregulates MAPK and Akt pathways indicating opposing effects of 15-LOX-1 [that isound to be overexpressed in prostate tumors] and 15-LOX-2 [found to be down regulated in prostate tumors] [43].

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