| Entity | Inflammation and cancer |
| Note | End product of arachidonic acid metabolism by the platelet-type 12-LOX 12(S)-Hydroxy eicosatetraenoic acid (12(S)-HETE) is shown to induce invasion, motility, and angiogenesis and protect tumour cells from apoptosis. Great many biological activities of 12(S)-HETE appear to be partly mediated by the activation of NF-kappaB. NF-kappaB is a family of five DNA binding proteins that regulate the expression of a variety of genes involved in host immune responses and inflammation. A direct relationship between platelet-type 12-LOX overexpression and NF-kappaB activation is reported in prostate cancer cells. |
| | |
| Entity | Polymorphisms associated with diseases |
| Note | Aberrant arachidonic acid metabolism by 12-lipoxygenase (12-LOX) is implicated in carcinogenesis. Genetic polymorphisms 12-LOX is therefore thought to influence its function and/or expression and may modify the risk for colorectal adenoma. One of the single nucleotide polymorphisms (SNPs) reported in the 12-LOX gene located in exon 6 resulting in an Arg to Gln substitution at amino acid 261 of 12-LOX is in a highly conserved region of the lipoxygenase domain. Data from a community-based, case-control study of incident, sporadic colorectal adenoma that included 162 cases and 211 controls have shown an inverse association between the Arg261Gln polymorphism in 12-LOX and colorectal adenoma (OR, 0.63; 95% CI, 0.40-1.00). A significant interaction also is observed between the 12-LOX polymorphism (Arg261Gln) and the use of nonsteroidal anti-inflammatory drugs. Another study argues that Gln261Arg in ALOX12 does not appear to be associated with colon cancer risk.
Studies have shown higher urinary excretion of the arachidonic acid-derived metabolite 12-(S)hydroxyeicosatetraenoic acid (12(S)-HETE) in essential hypertension. For analysis of the association of polymorphisms in ALOX12 with hypertension and urinary levels of 12(S)-HETE, a study with 200 patients with essential hypertension and 166 matched controls is performed and as a result, the distribution of genotypes of the R261Q (Arg to Gln) polymorphism is found to be significantly different between patients and controls. These results indicate that a nonsynonymous polymorphism in ALOX12 is associated to essential hypertension and to urinary levels of 12(S)-HETE.
Peak BMD is a major determinant of osteoporosis which is a complex disease with both genetic and environmental risk factors. In a population - and family - based association study of ALOX15 and ALOX12, SNPs distributed across the two genes are genotyped. Moderate evidence of association is found between spine BMD and six SNPs in the ALOX12 gene in both men and women. These data conclude that polymorphisms in the ALOX12 gene may contribute to normal variation in spine BMD. |
| | |
| Entity | Alzheimer's disease |
| Note | Alzheimer's disease (AD) is a chronic neurodegenerative disorder that impairs cognition and behavior. Although the initiating molecular events are not known, increasing evidence suggests that 12/15-LOX is a major source of oxidative stress which could play a functional role in pathogenesis. Quantitative Western blot analysis confirmed by immunohistochemical studies demonstrate that in affected frontal and temporal regions of AD brains, the amount of 12/15-LOX is higher compared to controls. Also metabolic products of 12/15-LOX are markedly elevated in AD brains compared to controls. |
| | |
| Entity | Bladder cancer |
| Note | 12-LOX expression is shown to be induced in bladder cancer tissues by an immunohistochemistry analysis. Also lipoxygenase inhibitors cause marked inhibition of bladder cancer cells in a concentration and time dependent manner. Cells treated with lipoxygenase inhibitors show chromatin condensation, cellular shrinkage, small membrane bound bodies (apoptotic bodies) and cytoplasmic condensation. |
| | |
| Entity | Testicular cancer |
| Note | 12-LOX is only slightly expressed in normal testis tissues, however, 12-LOX expression is found to be significant in testicular cancer tissues by immunohistochemistry studies. Specific LOX inhibitors have also been shown to inhibit the growth of testicular cancer in cell lines. |
| | |
| Entity | Prostate cancer |
| Note | Research focusing on mechanisms of action of 12-lipoxygenase in prostate cancer cells revealed that overexpression of 12-lipoxygenase in PC-3 cells results in a 3-fold increase in VEGF protein level when compared with vector control cells and there is an increase in PI3-kinase activity in 12-LOX-transfected PC-3 cells.
The expression of 12-LOX is detected to be low in benign prostatic hyperplasia and normal prostate tissues, whereas marked expression of 12-lipoxygenase is detected in prostatic intraepithelial neoplasia and prostate cancer tissues. The LOX inhibitors cause marked cellular death through apoptosis in prostate cancer cells in a concentration and time-dependent manner.
Another effect of 12-LOX in prostate cancer cells is that increase in 12-LOX expression enhances the metastatic potential of human prostate cancer cells. 12-LOX transfected PC-3 cells show a significant change in cell adhesiveness, spreading, motility, and invasiveness. |
| | |
| Entity | Breast cancer |
| Note | Total cellular RNA extraction from 64 frozen tissue samples of breast carcinoma and their corresponding normal adjacent tissues is performed for expression analysis of cyclooxygenase-2 and 12-lipooxygenase using RT-PCR. 62.5% of carcinoma samples showed over-expression of 12-lipooxygenase as compared to normal breast tissues. Results also reveal that and 12-lipooxygenase mRNA expressions are associated with TNM staging in human breast cancer.
A second study indicates that levels of 12- lipoxygenases together with 5-lipoxygenase are also particularly high in tumours from patients who died of breast cancer. Therefore raised level of 12-lipoxygenase might have prognostic value in patients with breast cancer. |
| | |
| Investigation of the oxygenation of phospholipids by the porcine leukocyte and human platelet arachidonate 12-lipoxygenases. |
| Takahashi Y, Glasgow WC, Suzuki H, Taketani Y, Yamamoto S, Anton M, Kˆºhn H, Brash AR |
| European journal of biochemistry / FEBS. 1993 ; 218 (1) : 165-171. |
| PMID 8243462 |
| |
| Arachidonate 12-lipoxygenase. |
| Yoshimoto T, Yamamoto S |
| Journal of lipid mediators and cell signalling. 1995 ; 12 (2-3) : 195-212. |
| PMID 8777566 |
| |
| Transcriptional activation of human 12-lipoxygenase gene promoter is mediated through Sp1 consensus sites in A431 cells. |
| Liu YW, Arakawa T, Yamamoto S, Chang WC |
| The Biochemical journal. 1997 ; 324 ( Pt 1) : 133-140. |
| PMID 9164849 |
| |
| Cloning of a human epidermal-type 12-lipoxygenase-related gene and chromosomal localization to 17p13. |
| Sun D, Elsea SH, Patel PI, Funk CD |
| Cytogenetics and cell genetics. 1998 ; 81 (1) : 79-82. |
| PMID 9691181 |
| |
| Characterization of epidermal 12(S) and 12(R) lipoxygenases. |
| McDonnell M, Li H, Funk CD |
| Advances in experimental medicine and biology. 2002 ; 507 : 147-153. |
| PMID 12664578 |
| |
| Levels of expression of lipoxygenases and cyclooxygenase-2 in human breast cancer. |
| Jiang WG, Douglas-Jones A, Mansel RE |
| Prostaglandins, leukotrienes, and essential fatty acids. 2003 ; 69 (4) : 275-281. |
| PMID 12907138 |
| |
| Platelet-type 12-lipoxygenase activates NF-kappaB in prostate cancer cells. |
| Kandouz M, Nie D, Pidgeon GP, Krishnamoorthy S, Maddipati KR, Honn KV |
| Prostaglandins & other lipid mediators. 2003 ; 71 (3-4) : 189-204. |
| PMID 14518561 |
| |
| Increased metastatic potential in human prostate carcinoma cells by overexpression of arachidonate 12-lipoxygenase. |
| Nie D, Nemeth J, Qiao Y, Zacharek A, Li L, Hanna K, Tang K, Hillman GG, Cher ML, Grignon DJ, Honn KV |
| Clinical & experimental metastasis. 2003 ; 20 (7) : 657-663. |
| PMID 14669797 |
| |
| Expression of lipoxygenase in human bladder carcinoma and growth inhibition by its inhibitors. |
| Yoshimura R, Matsuyama M, Tsuchida K, Kawahito Y, Sano H, Nakatani T |
| The Journal of urology. 2003 ; 170 (5) : 1994-1999. |
| PMID 14532840 |
| |
| Arachidonate lipoxygenase (ALOX) and cyclooxygenase (COX) polymorphisms and colon cancer risk. |
| Goodman JE, Bowman ED, Chanock SJ, Alberg AJ, Harris CC |
| Carcinogenesis. 2004 ; 25 (12) : 2467-2472. |
| PMID 15308583 |
| |
| Expression of lipoxygenase in human prostate cancer and growth reduction by its inhibitors. |
| Matsuyama M, Yoshimura R, Mitsuhashi M, Hase T, Tsuchida K, Takemoto Y, Kawahito Y, Sano H, Nakatani T |
| International journal of oncology. 2004 ; 24 (4) : 821-827. |
| PMID 15010818 |
| |
| 12/15-lipoxygenase is increased in Alzheimer's disease: possible involvement in brain oxidative stress. |
| Praticˆ¾ D, Zhukareva V, Yao Y, Uryu K, Funk CD, Lawson JA, Trojanowski JQ, Lee VM |
| The American journal of pathology. 2004 ; 164 (5) : 1655-1662. |
| PMID 15111312 |
| |
| Relationship between lipoxygenase and human testicular cancer. |
| Yoshimura R, Matsuyama M, Mitsuhashi M, Takemoto Y, Tsuchida K, Kawahito Y, Sano H, Nakatani T |
| International journal of molecular medicine. 2004 ; 13 (3) : 389-393. |
| PMID 14767568 |
| |
| Transcription factor Sp1 functions as an anchor protein in gene transcription of human 12(S)-lipoxygenase. |
| Chang WC, Chen BK |
| Biochemical and biophysical research communications. 2005 ; 338 (1) : 117-121. |
| PMID 16122700 |
| |
| Sp1 deacetylation induced by phorbol ester recruits p300 to activate 12(S)-lipoxygenase gene transcription. |
| Hung JJ, Wang YT, Chang WC |
| Molecular and cellular biology. 2006 ; 26 (5) : 1770-1785. |
| PMID 16478997 |
| |
| Human ALOX12, but not ALOX15, is associated with BMD in white men and women. |
| Ichikawa S, Koller DL, Johnson ML, Lai D, Xuei X, Edenberg HJ, Klein RF, Orwoll ES, Hui SL, Foroud TM, Peacock M, Econs MJ |
| Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2006 ; 21 (4) : 556-564. |
| PMID 16598376 |
| |
| Expression of cyclooxygenase-2 and 12-lipoxygenase in human breast cancer and their relationship with HER-2/neu and hormonal receptors: impact on prognosis and therapy. |
| Mohammad AM, Abdel HA, Abdel W, Ahmed AM, Wael T, Eiman G |
| Indian journal of cancer. 2006 ; 43 (4) : 163-168. |
| PMID 17192687 |
| |
| Mechanisms regulating tumor angiogenesis by 12-lipoxygenase in prostate cancer cells. |
| Nie D, Krishnamoorthy S, Jin R, Tang K, Chen Y, Qiao Y, Zacharek A, Guo Y, Milanini J, Pages G, Honn KV |
| The Journal of biological chemistry. 2006 ; 281 (27) : 18601-18609. |
| PMID 16638750 |
| |
| A coding polymorphism in the 12-lipoxygenase gene is associated to essential hypertension and urinary 12(S)-HETE. |
| Quintana LF, Guzmˆ°n B, Collado S, ClˆÝria J, Poch E |
| Kidney international. 2006 ; 69 (3) : 526-530. |
| PMID 16514435 |
| |
| Associations of functional polymorphisms in cyclooxygenase-2 and platelet 12-lipoxygenase with risk of occurrence and advanced disease status of colorectal cancer. |
| Tan W, Wu J, Zhang X, Guo Y, Liu J, Sun T, Zhang B, Zhao D, Yang M, Yu D, Lin D |
| Carcinogenesis. 2007 ; 28 (6) : 1197-1201. |
| PMID 17151091 |
| |
| Common polymorphisms in 5-lipoxygenase and 12-lipoxygenase genes and the risk of incident, sporadic colorectal adenoma. |
| Gong Z, Hebert JR, Bostick RM, Deng Z, Hurley TG, Dixon DA, Nitcheva D, Xie D |
| Cancer. 2007 ; 109 (5) : 849-857. |
| PMID 17236225 |
| |
