Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0376358 (prostate cancer)
59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Arachidonic acid (5,8,11,14-eicosatetraenoic acid), a member of the omega-6 poly-unsaturated fatty acids, was found to be an effective stimulator of human prostate cancer cell growth in vitro at micromolar concentrations. Selective blockade of the different metabolic pathways of arachidonic acid (e.g. ibuprofen for cyclooxygenase, SKF-525A for cytochrome P-450, baicalein and BHPP for 12-lipoxygenase, AA861 and MK886 for 5-lipoxygenase, etc.) revealed that the growth stimulatory effect of arachidonic acid is inhibited by the 5-lipoxygenase specific inhibitors, AA861 and MK886, but not by others. Addition of the eicosatetraenoid products of 5-lipoxygenase (5-HETEs) showed stimulation of prostate cancer cell growth similar to that of arachidonic acid, whereas the leukotrienes were ineffective. Moreover, the 5-series of eicosatetraenoids could reverse the growth inhibitory effect of MK886. Finally, prostate cancer cells fed with arachidonic acid showed a dramatic increase in the production of 5-HETEs which is effectively blocked by MK886. These experimental observations suggest that arachidonic acid needs to be metabolized through the 5-lipoxygenase pathway to produce 5-HETE series of eicosatetraenoids for its growth stimulatory effects on human prostate cancer cells.
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PMID:Arachidonic acid stimulates prostate cancer cell growth: critical role of 5-lipoxygenase. 919 9

Diets high in fat are associated with an increased risk of prostate cancer, although the molecular mechanism is still unknown. We have previously reported that arachidonic acid, an omega-6 fatty acid common in the Western diet, stimulates proliferation of prostate cancer cells through production of the 5-lipoxygenase metabolite, 5-HETE (5-hydroxyeicosatetraenoic acid). We now show that 5-HETE is also a potent survival factor for human prostate cancer cells. These cells constitutively produce 5-HETE in serum-free medium with no added stimulus. Exogenous arachidonate markedly increases the production of 5-HETE. Inhibition of 5-lipoxygenase by MK886 completely blocks 5-HETE production and induces massive apoptosis in both hormone-responsive (LNCaP) and -nonresponsive (PC3) human prostate cancer cells. This cell death is very rapid: cells treated with MK886 showed mitochondrial permeability transition between 30 and 60 min, externalization of phosphatidylserine within 2 hr, and degradation of DNA to nucleosomal subunits beginning within 2-4 hr posttreatment. Cell death was effectively blocked by the thiol antioxidant, N-acetyl-L-cysteine, but not by androgen, a powerful survival factor for prostate cancer cells. Apoptosis was specific for 5-lipoxygenase-programmed cell death was not observed with inhibitors of 12-lipoxygenase, cyclooxygenase, or cytochrome P450 pathways of arachidonic acid metabolism. Exogenous 5-HETE protects these cells from apoptosis induced by 5-lipoxygenase inhibitors, confirming a critical role of 5-lipoxygenase activity in the survival of these cells. These findings provide a possible molecular mechanism by which dietary fat may influence the progression of prostate cancer.
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PMID:Inhibition of arachidonate 5-lipoxygenase triggers massive apoptosis in human prostate cancer cells. 978 62

Multiple population-based studies show an increased risk of prostate cancer in populations that consume large amounts of animal fat. However, the molecular mechanisms linking dietary fat to prostate cancer biology remain obscure. Animal fats are typically rich sources of arachidonic acid and this fatty acid is converted to a wide range of powerful compounds including leukotrienes, prostaglandins, etc. We have shown that PC3 and LNCaP convert arachidonic acid to the 5-lipoxygenase product, 5-HETE. When the formation of 5-HETE is blocked, human prostate cancer cells enter apoptosis in less than 1 h and are dead within 2 h. Exogenous 5-HETE can rescue these cancer cells. These findings indicate that 5-HETE is a potent survival factor for human prostate cancer cells.
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PMID:Lipoxygenase inhibition in prostate cancer. 1032 95

It is well established that fatty acid metabolites of cyclooxygenase, lipoxygenase (LOX), and cytochrome P450 are implicated in essential aspects of cellular signaling including the induction of programmed cell death. Here we review the roles of enzymatic and non-enzymatic products of polyunsaturated fatty acids in controlling cell growth and apoptosis. Also, the spontaneous oxidation of polyunsaturated fatty acids yields reactive aldehydes and other products of lipid peroxidation that are potentially toxic to cells and may also signal apoptosis. Significant conflicting data in terms of the role of LOX enzymes are highlighted, prompting a re-evaluation of the relationship between LOX and prostate cancer cell survival. We include new data showing that LNCaP, PC3, and Du145 cells express much lower levels of 5-LOX mRNA and protein compared with normal prostate epithelial cells (NHP2) and primary prostate carcinoma cells (TP1). Although the 5-LOX activating protein inhibitor MK886 killed these cells, another 5-LOX inhibitor AA861 hardly showed any effect. These observations suggest that 5-LOX is unlikely to be a prostate cancer cell survival factor, implying that the mechanisms by which LOX inhibitors induce apoptosis are more complex than expected. This review also suggests several mechanisms involving peroxisome proliferator activated receptor activation, BCL proteins, thiol regulation, and mitochondrial and kinase signaling by which cell death may be produced in response to changes in non-esterified and non-protein bound fatty acid levels. Overall, this review provides a context within which the effects of fatty acids and fatty acid oxidation products on signal transduction pathways, particularly those involved in apoptosis, can be considered in terms of their overall importance relative to the much better studied protein or peptide signaling factors.
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PMID:Fatty acid oxidation and signaling in apoptosis. 1203 33

Metabolism of arachidonic acid through cyclooxygenase, lipoxygenase, or P450 epoxygenase pathways leads to the formation of various bioactive eicosanoids. In this review, we discuss alterations in expression pattern of eicosanoid-generating enzymes found during prostate tumor progression and expound upon their involvement in tumor cell proliferation, apoptosis, motility, and tumor angiogenesis. The expression of cyclooxygenase-2, 12-lipoxygenase, and 15-lipoxygenase-1 are up-regulated during prostate cancer progression. It has been demonstrated that inhibitors of cyclooxygenase-2, 5-lipoxygenase and 12-lipoxygenase cause tumor cell apoptosis, reduce tumor cell motility and invasiveness, or decrease tumor angiogenesis and growth. The eicosanoid product of 12-lipoxygenase, 12(S)-hydroeicosatetraenoic acid, is found to activate Erkl/2 kinases in LNCaP cells and PKCalpha in rat prostate AT2.1 tumor cells. Overexpression of 12-lipoxygenase and 15-lipoxygenase-1 in prostate cancer cells stimulate prostate tumor angiogenesis and growth, suggesting a facilitative role for 12-lipoxygenase and 15-lipoxygenase-1 in prostate tumor progression. The expression of 15-lipoxygenase-2 is found frequently to be lost during the initiation and progression of prostate tumors. 15(S)-hydroxyeicosatetraenoic acid, the product of 15-lipoxygenase-2, inhibits proliferation and causes apoptosis in human prostate cancer cells, suggesting an inhibitory role for 15-lipoxygenase-2 in prostate tumor progression. The regulation of prostate cancer progression by eicosanoids, in either positive or negative ways, provides an exciting possibility for management of this disease.
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PMID:Role of eicosanoids in prostate cancer progression. 1208 62

Previously, we reported that inhibition of arachidonate 5-lipoxygenase triggers massive apoptosis in both androgen-sensitive (LNCaP) and androgen-refractory (PC3) human prostate cancer cells within hours of treatment [Proc. Natl. Acad. Sci. USA 95 (1998) 13182-13187]. Apoptosis was prevented by exogenous 5(S)-HETE, a product of 5-lipoxygenase, indicating a role of this eicosanoid as an essential survival/anti-apoptotic factor for prostate cancer cells. However, nothing was clearly known about details of the underlying molecular mechanisms or events mediating the induction of fulminating apoptosis in these cells. This report documents the fact that inhibition of arachidonate 5-lipoxygenase induces rapid activation of c-Jun N-terminal kinase (JNK) in human prostate cancer cells which is prevented by the 5-lipoxygenase metabolite, 5(S)-HETE. Activation of JNK is unaffected by the cell-permeable tetra-peptide inhibitors of caspase 8 or caspase 3 (IETD-FMK and DEVD-FMK), though these inhibitors effectively blocked apoptosis triggering, suggesting that activation of JNK is independent or upstream of caspase activation. Both 5-lipoxygenase inhibition-induced activation of JNK and induction of apoptosis are prevented by curcumin, an inhibitor of JNK-signaling pathway. Apoptosis is also blocked by SP600125, a specific inhibitor of JNK activity, indicating that JNK activity is required for the induction of apoptosis in these cells. These findings suggest that the metabolites of arachidonate 5-lipoxygenase promote survival of prostate cancer cells involving down-regulation of stress-activated protein kinase.
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PMID:Inhibition of arachidonate 5-lipoxygenase triggers prostate cancer cell death through rapid activation of c-Jun N-terminal kinase. 1285 62

Recent clinical trials have documented that selenium significantly reduces the incidence of clinical prostate cancer. However, nothing is clearly known about the underlying molecular mechanisms by which selenium exerts its anti-cancer effect. This report provides evidence that selenium at micro-molar concentrations induces rapid apoptotic death in human prostate cancer cells, but not in normal prostate epithelial cells. Apoptosis involves activation of caspase 3 which plays a critical role in the cell death process. Interestingly, the apoptosis-inducing effect of selenium in prostate cancer cells is substantially alleviated by the 5-lipoxygenase metabolites, 5(S)-HETE and its dehydrogenated derivative 5-oxoETE, but not by metabolites of 12-lipoxygenase (12(S)-HETE) or 15-lipoxygenase (15(S)-HETE). Apoptosis is also prevented by their precursor, arachidonic acid, an omega-6, polyunsaturated fatty acid, presumably by metabolic conversion through the 5-lipoxygenase pathway. These results indicate that selenium's anticancer effect may involve induction of apoptosis specifically in prostate cancer cells sparing normal prostate epithelial cells, and that 5-lipoxygenase may be a molecular target of selenium's anticancer action. The present report warrants that care should be taken about high intake of dietary fat containing arachidonic acid or its precursor fatty acids when selenium is used for the management of prostate cancer, and suggests that a combination of selenium and 5-lipoxygenase inhibitors may be a more effective regimen for prostate cancer control.
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PMID:Rapid induction of apoptosis in prostate cancer cells by selenium: reversal by metabolites of arachidonate 5-lipoxygenase. 1497 47

The aims of this study were to examine the anti-proliferative effects of different concentrations of a commercial preparation of conjugated linoleic acids (CLA) mixture of isomers [cis-9, trans-11 CLA (c9,t11 CLA): trans-10, cis-12 CLA (50:50)] and their constituent isomers on PC-3, a human prostatic carcinoma cell line, and to study their effects on gene expression (mRNA and protein levels) of different enzymes and oncoproteins involved in oncogenesis and progression of prostate cancer. This includes pathways for arachidonic acid metabolism [cyclooxygenase 1 (COX-1), 2 (COX-2) and 5-lipoxygenase (5-LOX)], apoptosis (bcl-2) and cell cycle control (p21(WAF/Cip1)). Our results indicate a significant decrease in PC-3 proliferation elicited by CLA, although with high variability between isomers. The trans-10, cis-12 CLA was the most effective isomer (55% inhibition). This isomer was also able to decrease bcl-2 gene expression and to increase p21(WAF1/Cip1) mRNA levels (60% increase at highest concentration). In contrast, cis-9, trans-11 had no effect on these proteins but had a clear effect on 5-LOX expression and to a lesser degree on COX-2 protein level isomers. In conclusion, the anti-proliferative effects on PC-3 of CLA mixture and their constituent isomers are not equivalent, due to the different pathways involved for individual isomers. Trans-10, cis-12 seems to work preferentially through modulation of apoptosis and cell cycle control, while c9,t11 CLA isomer affects arachidonic acid metabolism.
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PMID:Conjugated linoleic acids (CLAs) decrease prostate cancer cell proliferation: different molecular mechanisms for cis-9, trans-11 and trans-10, cis-12 isomers. 1497 30

Recent studies have demonstrated that lipoxygenase (LOX) inhibitor induces growth arrest of cancer cells through apoptosis. In this study, we examined the effects of LOX inhibitors on cell proliferation in renal cell carcinoma (RCC), bladder tumor (BT), and prostate cancer (PC) cell lines. We investigated the inhibitory effect of LOX inhibitors, 5-, 12- and non-specific LOX inhibitor on RCC, BT and PC-derived cell lines using MTT assay and Hoechst staining. All LOX inhibitors induced the reduction of cell viability with the half-maximal concentration of growth inhibition of RCC, BT, and PC cell lines. Furthermore, counting cells at days 1, 2 and 3, clearly showed marked inhibition of cell proliferation by treatment with non-specific and 5-LOX inhibitor. All LOX inhibitors stopped the growth of all RCC, BT and PC cells. The effect of non-specific LOX inhibitor was strongest. The effect of 5-LOX inhibitor was stronger than 12-LOX inhibitor. All LOX inhibitors caused marked inhibition of urological cancer cells through apoptosis. LOX inhibitor may mediate potent antiproliferative effects against RCC, BT and PC cells through differentiation. Thus, LOX inhibitor, especially 5-LOX inhibitor may become a new target in treatment of urological cancers.
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PMID:Lipoxygenase inhibitors prevent urological cancer cell growth. 1506 67

The incidence of prostate carcinoma is very low in Eastern countries, such as Japan, suggesting that life style conditions may play a crucial role in the development of this pathology. Dietary omega-6 polyunsaturated fatty acids, such as linoleic (LA) and arachidonic (AA) acids, have been shown to stimulate the proliferation of prostate cancer cells after being converted into 5-HETE by means of the 5-lipoxygenase (5-LOX) pathway. Blockade of 5-LOX activity has been proposed as an attractive target for the prevention of the mitogenic action of dietary fats on prostate cancer. The 5-LOX gene has been shown to carry a response element for the orphan nuclear receptor RORalpha (for its RORalpha1 isoform in particular) in its promoter region. We attempt to clarify whether activation of RORalpha might modulate the expression of 5-LOX, thus interfering with the mitogenic activity of fatty acids in prostate cancer cells. We show that in androgen-independent DU 145 prostate cancer cells, LA, AA and their metabolite 5-HETE exert a strong stimulatory action on cell proliferation. This effect is completely counteracted by the simultaneous treatment of the cells with a non redox inhibitor of 5-LOX activity. We then demonstrate that: i) RORalpha, and specifically its RORalpha1 isoform, is expressed in DU 145 cells; ii) activation of RORalpha, by means of the thiazolidinedione derivative CGP 52608 (the synthetic RORalpha activator), significantly reduces 5-LOX expression, both at mRNA (as evaluated by comparative RT-PCR) and at protein (as investigated by Western blot analysis) level (this was confirmed by the reduced activity of 5-LOX in CGP 52608 treated cells); and iii) the treatment of DU 145 cells with CGP 52608 completely abrogated the proliferative action of both LA and AA. These results have been confirmed in another androgen-independent prostate cancer cell line (PC3). Our data indicate that, by decreasing the expression of 5-LOX, activation of RORalpha might interfere with the mitogenic activity of fatty acids on prostate cancer. We have shown previously that CGP 52608 reduces the proliferation and the metastatic behavior of DU 145 cells. These observations indicate that the orphan nuclear receptor RORalpha might be considered as a molecular target for the development of new chemopreventive or chemotherapeutic strategies for prostate carcinoma.
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PMID:Activation of the orphan nuclear receptor RORalpha counteracts the proliferative effect of fatty acids on prostate cancer cells: crucial role of 5-lipoxygenase. 1530 79


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