12-Lipoxygenase Induces Apoptosis of Human Gastric Cancer AGS Cells via the ERK1/2 Signal Pathway

Chen, Fenglin; Wang, Xiaozhong; Li, Jianying; Yu, Jie-Ping; Huang, Chuanbing; Chen, Zhuo

doi:10.1007/s10620-007-9841-1

Cited by 36 publications

(30 citation statements)

References 14 publications

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“…12-LOX and its metabolites have been shown to promote cancer progression and metastasis through a MAPK-dependent pathway (Szekeres et al, 2000;Ding et al, 2001). Inhibition of 12-LOX in tumor cells was shown to induce apoptosis and was blocked by either overexpression of 12-LOX or addition of 12-HETE (Szekeres et al, 2000;Chen et al, 2008). In platelets, however, the underlying signaling mechanisms regulating 12-LOX-mediated platelet reactivity have not been well characterized.…”

Section: Discussionmentioning

confidence: 99%

Protein Kinase C Regulation of 12-Lipoxygenase-Mediated Human Platelet Activation

et al. 2011

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Platelet activation is important in the regulation of hemostasis and thrombosis. Uncontrolled activation of platelets may lead to arterial thrombosis, which is a major cause of myocardial infarction and stroke. After activation, metabolism of arachidonic acid (AA) by 12-lipoxygenase (12-LOX) may play a significant role in regulating the degree and stability of platelet activation because inhibition of 12-LOX significantly attenuates platelet aggregation in response to various agonists. Protein kinase C (PKC) activation is also known to be an important regulator of platelet activity. Using a newly developed selective inhibitor for 12-LOX and a pan-PKC inhibitor, we investigated the role of PKC in 12-LOX-mediated regulation of agonist signaling in the platelet. To determine the role of PKC within the 12-LOX pathway, a number of biochemical endpoints were measured, including platelet aggregation, calcium mobilization, and integrin activation. Inhibition of 12-LOX or PKC resulted in inhibition of dense granule secretion and attenuation of both aggregation and ␣IIb␤ 3 activation. However, activation of PKC downstream of 12-LOX inhibition rescued agonist-induced aggregation and integrin activation. Furthermore, inhibition of 12-LOX had no effect on PKC-mediated aggregation, indicating that 12-LOX is upstream of PKC. These studies support an essential role for PKC downstream of 12-LOX activation in human platelets and suggest 12-LOX as a possible target for antiplatelet therapy.

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Section: Discussionmentioning

confidence: 99%

Protein Kinase C Regulation of 12-Lipoxygenase-Mediated Human Platelet Activation

et al. 2011

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“…12-LO has been repeatedly implicated in carcinogenesis (55)(56)(57), atherosclerosis (58)(59)(60), hypertension (61,62), and stroke (63,64). Increased biosynthesis of 12(S)-HPETE, the major 12-LO product of AA oxygenation, led, for example, to upregulation of protein kinase C-a via a receptor-mediated mechanism (65) and NF-k-B (66) in certain types of cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of lipoxygenases and cyclooxygenases by linoleyl hydroxamic acid: comparative in vitro studies

Butovich

Lukyanova

2008

Journal of Lipid Research

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In this first comparative in vitro study, linoleyl hydroxamic acid (LHA), a simple and stable derivative of linoleic acid, was tested as an inhibitor of several enzymes involved in arachidonic acid metabolism in mammals. The tested enzymes were human recombinant 5-lipoxygenase (h5-LO), porcine leukocyte 12-LO, rabbit reticulocyte 15-LO, ovine cyclooxygenases 1/2 (COX1/COX2), and human microsomal prostaglandin E synthase-1 (mPGES-1). Potato tuber and soybean lipoxygenases (ptLOX and sLOX, respectively) were studied for comparative purposes. LHA inhibited most of the tested enzymes with the exception of mPGES-1. The LHA inhibitory activity increased as follows: mPGES-1 (no inhibition),,COX1 5 COX2,h5-LO 5 sLOX 5 ptLOX, 12-LO,,15-LO. The IC 50 values for COX1/COX2, h5-LO, 12-LO, and 15-LO were 60, 7, 0.6, and 0.02 mM, respectively. sLOX was the only tested enzyme that was capable of aerobic oxygenation of LHA, producing 13-hydroperoxy-LHA. The enzyme rapidly inactivated during the reaction. Therefore, LHA could be used as an effective LO/LOX inhibitor without affecting COX1/COX2 and mPGES-1. Possible implications of this observation include treating diseases and pathological states that are caused by (or lead to) hyperproduction of LO-derived metabolites, e.g., inflammation, cardiovascular disorders, cancer, asthma, allergies, psoriasis, and stroke.-Butovich, I. A., and S. M. Lukyanova. Inhibition of lipoxygenases and cyclooxygenases by linoleyl hydroxamic acid: comparative in vitro studies.

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“…involvement of the lOx pathway in cancer, including breast cancer, has been reported, and studies have unequivocally shown a link between the lOx pathway and cancer. up-regulated expression of lOxs has been determined in both animal models of cancer (32) and in humans (7,30). Jiang et al (36) and mohammad et al (37) showed increased levels of alOx12 in breast cancer.…”

Section: Discussionmentioning

confidence: 99%

“…Several lines of evidence have implicated alOxs and their products in various pathologies linked with inflammation, including Alzheimer's disease (23,24), atherosclerosis (25,26), hypertension (27), stroke (27)(28)(29) and cancer (7). Evidence links up-regulated alOx12 expression to the development of cancer, sustenance, growth and metastasis (11,(30)(31)(32)(33)(34). Overexpression of alOx12 has been demonstrated in various types of cancers, including breast, renal, pancreatic and prostate (13,(35)(36)(37).…”

Section: Introductionmentioning

confidence: 99%

Association of a functional polymorphism (Gln261Arg) in 12-lipoxygenase with breast cancer

Prasad

Kolli

Moganti

2011

Experimental and Therapeutic Medicine

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Abstract. the overexpression of arachidonyl lipoxygenase-12 (alOx12) in breast cancer has been reported. hence, we examined whether a non-synonymous polymorphism of alOx12 (mrna, a835G; Gln261arg) is associated with breast cancer in females. the polymorphism was detected in genomic dna by pcr-rFlp. the association between the a835G polymorphism and breast cancer risk was measured by odds ratio (OR) with 95% confidence intervals (CIs) using Fisher's exact test, and differences were considered significant at p<0.05. the frequencies of aa (wild-type), GG (homozygous variant) and aG (heterozygous variant) were 59.5, 0.9 and 39.6% in the controls, and 39.3, 2.5 and 58.2% in the breast cancer cases, respectively. the frequency of the aG genotype was higher in the patients compared to the controls (p<0.0014). the frequency of the GG variant was 2.5 and 0.9% in the cancer subjects and controls, respectively. the relative risk of breast cancer was 2 times greater (Or=2.227) at 95% ci when compared to the relative risk of the heterozygous variant. For the GG genotype, the risk was 4 times greater (Or=4.125) at 95% ci than that of the controls, suggesting a positive association of the aG genotype with the occurrence of breast cancer. the frequencies of the polymorphism were different in different populations. the arg/Gln and arg/arg variants were associated with an increased risk of breast cancer, and the frequencies of the variants differed considerably among various populations. The identification of a gene with links to breast cancer may impact screening, diagnosis and drug development.

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12-Lipoxygenase Induces Apoptosis of Human Gastric Cancer AGS Cells via the ERK1/2 Signal Pathway

Cited by 36 publications

References 14 publications

Protein Kinase C Regulation of 12-Lipoxygenase-Mediated Human Platelet Activation

Protein Kinase C Regulation of 12-Lipoxygenase-Mediated Human Platelet Activation

Inhibition of lipoxygenases and cyclooxygenases by linoleyl hydroxamic acid: comparative in vitro studies

Association of a functional polymorphism (Gln261Arg) in 12-lipoxygenase with breast cancer

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