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].