Disease relevance of ALOX12

• 12-LOX metabolizes arachidonic acid to 12(S)-hydroxyeicosateraenoic acid (12(S)-HETE), which induces a number of cellular responses associated with tumor progression and metastasis [1].
• We screened a yeast two-hybrid interaction library from human epidermoid carcinoma A431 cells and identified four cellular proteins that interact specifically with 12-LOX [1].
• Expressions of 5- and 12-LOX in prostate cancer (PC) patients, prostatic intraepithelial neoplasia (PIN), benign prostatic hyperplasia (BPH), and normal prostate (NP) tissues were examined, as well as effects of their inhibitors on cell proliferation in 2 PC cell lines (PC3, DU-145) [2].
• The targeting of 12-LOX in neuroblastoma cells may thus be a novel pathway for the development of drugs inducing apoptosis of neuroblastoma with improved tumor specificity [3].
• We have studied the differences in 12-LOX protein expression during the progression of melanoma from human melanocytic cells to benign and dysplastic naevi to malignant metastatic disease [4].

Psychiatry related information on ALOX12

• Association of a new polymorphism in ALOX12 gene with bipolar disorder [5].

High impact information on ALOX12

• The very limited current data on the role of lipoxygenase (LOX) metabolism in tumorigenesis suggests that the oxidative metabolism of linoleic and arachidonic acid possibly shifts from producing antitumorigenic 15-LOX-1 and 15-LOX-2 products to producing protumorigenic 5-LOX and 12-LOX products [6].
• Here, using an antisense oligonucleotide-based strategy, we show that blockade of 12-LOX expression prevents both A beta-induced apoptosis and overexpression of c-Jun, a factor required for the apoptotic process, in cortical neurons [7].
• The results show that 12-LOX regulates cell survival and apoptosis by affecting the expression and localization of the vitronectin receptors, alpha(v)beta(3) and alpha(v)beta(5), in two cancer cell lines [8].
• Furthermore, Baicalein or N-benzyl-N-hydroxy-5-phenylpentamide, specific 12-LOX inhibitors, significantly decreased alpha(v)beta(5)-mediated adhesion and survival in 12-LOX-overexpressing cells [8].
• PC3 cells transfected with 12-LOX displayed increased alpha(v)beta(3) and alpha(v)beta(5) integrin expression, whereas other integrins were unaltered [8].

Chemical compound and disease context of ALOX12

• Arachidonate 12-lipoxygenase (LOX) converts arachidonic acid to 12(S)-hydroxyeicosatetraenoic acid (HETE), a bioactive lipid implicated in tumor angiogenesis, growth, and metastasis [9].
• 12-Lipoxygenase (12-LOX), through its metabolite 12( )-hydroxyeicosatetraenoic acid [12( )-HETE], has been demonstrated to play a pivotal role in experimental melanoma invasion and metastasis, and 12-LOX expression may be important in early human melanoma carcinogenesis [4].
• The aim of this study was to analyze the association of polymorphisms in ALOX12 with hypertension and urinary levels of 12(S)-HETE [10].
• The effect of two 12-LOX inhibitors, Baicalein and N-benzyl-N-hydroxy-5-phenylpentamide (BHPP), on the mechanisms controlling cell cycle progression and apoptosis were examined in two prostate cancer cell lines, PC3 and DU-145 [11].
• The general LOX inhibitor NDGA, the 5-LOX inhibitor Rev5901, and the 12-LOX inhibitor baicalein all induced apoptosis in all four pancreatic cancer cell lines, as confirmed by all three methods, suggesting that both the 5-LOX and 12-LOX pathways are important for survival of these cells [12].

Biological context of ALOX12

• RESULTS: Moderate evidence of association was found between spine BMD and six SNPs in the ALOX12 gene in both men and women (p = 0.0052-0.050) [13].
• Furthermore, the most common SNP haplotype in ALOX12 showed evidence of significant association with high spine BMD in men (p = 0.0083), whereas the second most common haplotype was associated with high spine BMD in women (p = 0.0081) [13].
• Linkage analysis assigned S0601 distal to ALOX12 on SSC12, providing further evidence for the conservation of synteny between HSA17 and SSC12 [14].
• Arachidonate 12-lipoxygenase purified from porcine leukocytes and human platelets, 15-lipoxygenase from rabbit reticulocytes and fatty acid cyclooxygenase from bovine vesicular glands were inhibited by the compound only at higher concentrations (IC50 = 2.3, 11, 5.2 and 2.5 microM, respectively) [15].
• The apoptotic effect of BMD188 in prostate cancer cells does not depend on cell cycle, p53 status, or its purported target, arachidonate 12-lipoxygenase, but does require caspase activation and seems to involve mitochondria [16].

Anatomical context of ALOX12

• Here, we demonstrated that keratin 5, a 58 kD protein required for formation of 8 nm intermediate filaments, binds to 12-LOX in human tumor cells and may contribute to the regulated trafficking of 12-LOX [1].
• Immunocytochemical localization of platelet-type arachidonate 12-lipoxygenase in mouse blood cells [17].
• Subcellular localization of arachidonate 12-lipoxygenase and morphological effect of its overexpression on murine keratinocytes [18].
• 12-LOX expression was significantly different between compound naevus and dysplastic naevus melanocytes ( = 0.01) [4].
• The arachidonate 12-lipoxygenase of human platelets, the recombinant arachidonate 5-lipoxygenase of human leukocyte, and the soybean lipoxygenase I were less effective in oxidizing human LDL [19].

Associations of ALOX12 with chemical compounds

• We identified type II keratin 5, lamin A, the cytoplasmic domain of integrin beta4 subunit and a phosphoprotein C8FW as 12-LOX interacting proteins [1].
• Arachidonate 12-lipoxygenase introduces a molecular oxygen into the C-12 position of arachidonic acid to produce 12(S)-hydroperoxy-5,8,10,14-eicosatetraenoic acid [20].
• Using specific inhibitors of LOX, blocking 12-LOX but not 5- or 15-LOX inhibited both fenretinide-induced ROS and apoptosis [3].
• The increased spreading of 12-LOX transfected PC-3 cells was blocked by treatment with 12-LOX inhibitors, baicalein and CDC [9].
• Inhibition of 12-lipoxygenase (12-LOX), but not cyclooxygenases, blocked monocyte adhesion, and addition of 12-hydroxyeicosatetraenoic acid (12-HETE) mimicked the effects of oxidized phospholipids [21].

Other interactions of ALOX12

• These targets include procarcinogenic lipoxygenases (LOXs), including 5-, 8-, and 12-LOX, and anticarcinogenic LOXs, including 15-LOX-1 and possibly 15-LOX-2 [22].
• 12-LOX expression was determined in normal human skin melanocytes and in melanocytes found in compound naevi, dysplastic naevi and melanomas using a platelet-type 12-LOX antibody with a diaminobenzidine immunoperoxidase system detection system and was quantified using the analysis software NIH Image 1.62 [4].
• Also, following GPVI activation, 12-LOX co-immunoprecipitates with both cytosolic and secretory PLA2 (sPLA2) [23].
• Subsequently, it is found that the levels of COX-2 and/or 12-LOX are frequently increased in various cancers [24].
• Out of six polymorphisms in the coding region of ALOX12, only R261Q determined a nonconservative amino-acid change and was evaluated by polymerase chain reaction and restriction digestion [10].

Analytical, diagnostic and therapeutic context of ALOX12

• Expression of 5- and 12-LOX protein was detected by immunohistochemistry [2].
• Molecular cloning and expression of human arachidonate 12-lipoxygenase [25].
• By using reverse transcriptase-polymerase chain reaction, sequencing and various immunological techniques we have demonstrated conclusively the expression of the platelet-type 12-LOX in human melanoma cells of different origin, in their transplanted xenografts and in fresh human skin tumors [26].
• These data suggest that 12-LOX may be an important novel marker for cancer progression within the melanoma system, and therefore could be a useful biomarker and therapeutic target for melanoma chemoprevention [4].
• However, when 5-LOXAP was considered together with 12-LOX, it improved the predictive power for both overall and disease-free survival (109.0 month vs. 143.1 months, P = 0.0156 for overall survival and 98.3 months vs. 141.3 months for disease-free survival, P = 0.0022) [27].

References