HMG-CoA reductase inhibitors induce COX-2 gene expression in murine macrophages: role of MAPK cascades and promoter elements for CREB and C/EBPβ

Chen, Jui-Ching; Huang, Kuo‐Chin; Wingerd, Byron A.; Wu, Wen-Tung; Lin, Wan-Wan

doi:10.1016/j.yexcr.2004.05.039

Cited by 51 publications

(38 citation statements)

References 69 publications

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“…This site, termed the carbohydrate response element, is located upstream of the insulin response sequence and includes a CCAAT box that binds CCAAT enhancer-binding protein (C/EBP). Interestingly, statins have been shown to augment the transcription of CCAAT-containing genes, such as, tumor necrosis factor-␣, interleukin-12p40, and cyclooxygenase-2, in a (C/EBP)-dependent manner (45,46). Furthermore, similar to the results obtained in the present study, the effects of statins on interleukin-12p40 could be reversed by mevalonate and isoprenoids but not by sterols (45).…”

Section: Discussionsupporting

confidence: 82%

Regulation of Fatty Acid Synthesis by Farnesyl Pyrophosphate

Murthy¹,

Tong²,

Hohl

2005

Journal of Biological Chemistry

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Fatty acid biosynthesis is transcriptionally regulated by liver X receptor (LXR) and its gene target, sterol regulatory element binding protein-1c (SREBP-1c). LXR activation is induced by oxysterol end products of the mevalonate pathway and is inhibited by the upstream non-sterol isoprenoid, geranylgeranyl pyrophosphate (GGPP). Whether isoprenoids play a role in regulating the transcription of genes involved in fatty acid biosynthesis is unknown. In CaCo-2 colon epithelial cells, depletion of mevalonate and its derivatives, including oxysterol ligands for LXR, increased fatty acid synthesis. Addition of mevalonate or its isoprenoid derivative, farnesyl pyrophosphate (FPP), prevented this increase. The effects of FPP were likely due to itself or its degradation products, because none of its downstream derivatives, GGPP, ubiquinone, or cholesterol, were effective. Moreover, the effects of FPP could not be accounted for by protein prenylation, because inhibition of farnesylation did not alter fatty acid synthesis in mevalonate-depleted cells incubated with the isoprenoid. Neither was fatty acid synthesis in these cells altered by inhibition of ␤-oxidation. Mevalonate depletion increased fatty acid synthase (FAS) mRNA by transcriptional mechanisms, without increasing gene expression of other enzymes involved in fatty acid biosynthesis or of SREBP-1c. The abundance of mature SREBP-2 but not SREBP-1 was increased following mevalonate depletion. FPP prevented the increase in FAS mRNA in mevalonate-depleted cells without altering SREBP-2 activation. Thus, FPP regulates fatty acid synthesis by a mechanism that is likely independent of the SREBP pathway.The biosynthesis of fatty acids and cholesterol are closely related. Enzymes catalyzing the synthesis and metabolism of both lipids are coordinately regulated by the same transcription factors, the sterol regulatory element-binding proteins (SREBPs) 2 and the liver X receptors (LXRs) (1-3). LXRs belong to a superfamily of nuclear hormone receptors that are ligand-activated transcription factors (3). They form obligate heterodimers with retinoid X receptors (RXRs), another member of this receptor family, and subsequently bind to specific response ele-

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Section: Discussionsupporting

confidence: 82%

Regulation of Fatty Acid Synthesis by Farnesyl Pyrophosphate

Murthy¹,

Tong²,

Hohl

2005

Journal of Biological Chemistry

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“…We observed both phenomena. In addition, although others (31,32) have shown higher concentrations (10 or 20 Amol/L) of lovastatin and simvastatin induced COX-2 protein expression in various cell lines, our data showed that a low concentration (2 Amol/L) of lovastatin and simvastatin also induced COX-2 expression in prostate cancer cell lines. Moreover, our data suggested that inactivation of RhoA may be the molecular mechanism by which statin mediates its antitumor activity.…”

Section: Discussioncontrasting

confidence: 76%

Statin Induces Apoptosis and Cell Growth Arrest in Prostate Cancer Cells

Hoque

Chen

Xu³

2008

Cancer Epidemiology, Biomarkers &Amp; Prevention

189

136

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Statins are a class of low molecular weight drugs that inhibit the rate-limiting enzyme of the mevalonate pathway 3-hydroxy-3-methylglutaryl-CoA reductase. Statins have been approved and effectively used to control hypercholesterolemia in clinical setting. Recent study showed statin's antitumor activity and suggested a potential role for prevention of human cancers. In this study, we did cell viability, DNA fragmentation, and terminal deoxynucleotidyl transferase -mediated dUTP nick-end labeling assays to evaluate the action of statins on prostate cancer cells and used Western blotting and RhoA activation assay to investigate the underlying molecular mechanism of action. Our data showed that lovastatin and simvastatin effectively decreased cell viability in three prostate cancer cell lines (PC3, DU145, and LnCap) by inducing apoptosis and cell growth arrest at G 1 phase. Both lovastatin and simvastatin induced activation of caspase-8, caspase-3, and, to a lesser extent, caspase-9. Both statins suppressed expression of Rb, phosphorylated Rb, cyclin D1, cyclin D3, CDK4, and CDK6, but induced p21 and p27 expression in prostate cancer cells. Furthermore, lovastatin and simvastatin suppressed RhoA activation and c-JUN expression, but not cyclooxygenase-2 expression. Our data showed that the antitumor activity of statins is due to induction of apoptosis and cell growth arrest. The underlying molecular mechanism of statin's action is mediated through inactivation of RhoA, which in turn induces caspase enzymatic activity and/or G 1 cell cycle. Future studies should focus on examining statins and other apoptosisinducing drugs (e.g., cyclooxygenase-2 inhibitors or curcumin) together to assess their efficacy in prevention of prostate cancer. (Cancer Epidemiol Biomarkers Prev 2008;17(1):88 -94)

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“…Here, we showed that cell deathpromoting effect of AICAR might not be mediated through the inhibition of HMG-CoA reductase. We have observed that exogenous mevalonate did not overcome the deathinducing effect of AICAR, although it can prevent biological outcome of statins (24,35).…”

Section: Discussionmentioning

confidence: 87%

5-Aminoimidazole-4-carboxamide riboside sensitizes TRAIL- and TNFα-induced cytotoxicity in colon cancer cells through AMP-activated protein kinase signaling

Chao

Chen

et al. 2007

Molecular Cancer Therapeutics

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Death receptor-mediated tumor cell death, either alone or in combination with other anticancer drugs, is considered as a new strategy for anticancer therapy. In this study, we have investigated the effects and molecular mechanisms of 5-aminoimidazole-4-carboxamide riboside [AICAR; a pharmacologic activator of AMP-activated protein kinase (AMPK)] in sensitizing tumor necrosis factor (TNF) -related apoptosis-inducing ligand (TRAIL) -and TNFA-induced apoptosis of human colon cancer HCT116 cells. The cytotoxic action of AICAR requires AMPK activation and may occur at various stages of apoptotic pathways. AICAR cotreatment with either TRAIL or TNFA enhances activities of caspase-8, caspase-9, and caspase-3; down-regulates the antiapoptotic protein Bcl-2; increases the cleavage of Bid and results in the decrease of mitochondrial membrane potential; potentiates activation of p38 and c-Jun NH 2 -terminal kinase; and inhibits nuclear factor-KB activity. In addition, this sensitized cell apoptosis was neither observed in p53-null HCT116 cells nor affected by the cotreatment with mevalonate. In summary, we have developed a novel strategy of combining AICAR with TRAIL for the treatment of colon cancer cells. The sensitization effect of AICAR in cell apoptosis was mediated through AMPK pathway, requires p53 activity, and involves mitochondria-dependent apoptotic cascades, p38 and c-Jun NH 2 -terminal kinase. [Mol Cancer Ther 2007;6(5):1562 -71]

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HMG-CoA reductase inhibitors induce COX-2 gene expression in murine macrophages: role of MAPK cascades and promoter elements for CREB and C/EBPβ

Cited by 51 publications

References 69 publications

Regulation of Fatty Acid Synthesis by Farnesyl Pyrophosphate

Regulation of Fatty Acid Synthesis by Farnesyl Pyrophosphate

Statin Induces Apoptosis and Cell Growth Arrest in Prostate Cancer Cells

5-Aminoimidazole-4-carboxamide riboside sensitizes TRAIL- and TNFα-induced cytotoxicity in colon cancer cells through AMP-activated protein kinase signaling

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