Importance of mevalonate‐derived products in the control of HMG‐CoA reductase activity and growth of human lung adenocarcinoma cell line a549

Bennis, Faïza; Favre, Gilles; Gaillard, F; Soula, G

doi:10.1002/ijc.2910550421

Cited by 73 publications

(43 citation statements)

References 29 publications

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“…We demonstrated that the expression level of HMG-CoA mRNA in colon cancer tissues is greater than that in the uninvolved mucosa. Similar observations have been reported in leukemia cells (52) and lung cancer cells (53). In addition, our study shows that there is a correlation between HMG-CoA mRNA expression and survivin mRNA expression in colon cancer tissues.…”

Section: Discussionsupporting

confidence: 92%

Survivin Down-regulation Plays a Crucial Role in 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Inhibitor-induced Apoptosis in Cancer

Kaneko¹,

Tsuji²,

Asanuma

et al. 2007

Journal of Biological Chemistry

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3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (HRIs) are widely used to reduce serum cholesterol in patients with hypercholesterolemia. Previous studies have shown that HRIs can induce apoptosis in colon cancer cells. In this study, we investigated the mechanisms underlying the apoptosis-inducing effect of HRIs in greater detail. The HRI lovastatin induced apoptosis in the human colon cancer cell line SW480 by blocking the cholesterol synthesis pathway. Immunoblot analysis of antiapoptotic molecules, including survivin, XIAP, cIAP-1, cIAP-2, Bcl-2, and Bcl-X L , revealed that only survivin expression was decreased by lovastatin. Survivin downregulation by RNA interference induced apoptosis, and survivin overexpression rendered the cells resistant to lovastatin-induced growth inhibition. These results indicate that survivin downregulation contributes substantially to the proapoptotic properties of lovastatin. Farnesyl pyrophosphate and geranylgeranyl pyrophosphate, two downstream intermediates in the cholesterol synthesis pathway, simultaneously reversed survivin down-regulation and the blocking of Ras isoprenylation by lovastatin. Ras isoprenylation is important for the activation of Ras-mediated signaling, including the activation of the phosphatidylinositol 3-kinase (PI3-kinase)/Akt pathway. The PI3-kinase inhibitor down-regulated survivin in SW480 cells. In addition, lovastatin blocked Ras activation and Akt phosphorylation. We conclude that survivin down-regulation is crucial in lovastatin-induced apoptosis in cancer cells and that lovastatin decreases survivin expression by inhibiting Ras-mediated PI3-kinase activation via the blocking of Ras isoprenylation.3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) 3 reductase inhibitors (HRIs) are widely used to reduce serum cholesterol and are well tolerated by patients with hypercholesterolemia (1). HRIs prevent the formation of mevalonate from HMG-CoA by inhibiting the enzyme HMG-CoA reductase, thereby inhibiting cholesterol synthesis (2). In large clinical trials designed to study the changes in coronary events in coronary heart disease patients receiving HRIs, the number of newly diagnosed colon cancer cases showed a reduction of between 43% (3) and 19% (4) during a 5-year follow-up period. It has been reported that HRIs could induce apoptosis in colon cancer cells (5-7). Farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), two downstream intermediates in the cholesterol synthesis pathway, belong to a class of compounds named isoprenoids. They are bound to several cellular proteins, including small GTPases such as Ras, Rho, and Rac, by a posttranslational modification known as isoprenylation. This process involves the addition of a 15-carbon farnesyl chain in FPP (farnesylation) or a 20-carbon geranylgeranyl chain in GGPP (geranylgeranylation) to a cysteine sulfhydryl group near the carboxyl terminus. Isoprenylation of these proteins is crucial for membrane attachment (8, 9) and the subsequent acquisition of biological activity (10)...

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Section: Discussionsupporting

confidence: 92%

Survivin Down-regulation Plays a Crucial Role in 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Inhibitor-induced Apoptosis in Cancer

Kaneko¹,

Tsuji²,

Asanuma

et al. 2007

Journal of Biological Chemistry

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“…including prostate cancer and oral cancer [48,49], and dysregulated in lung and breast cancers [50,51]. Our data indicating that MDA-MB-231, that is highly aggressive tumor type representative, has an higher concentration of cholesterol in rafts and resistance to PUFA incorporation are in line to above cited reports.…”

supporting

confidence: 91%

Chemical–Physical Changes in Cell Membrane Microdomains of Breast Cancer Cells After Omega-3 PUFA Incorporation

Corsetto

Cremona

Montorfano

et al. 2012

Cell Biochem Biophys

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“…[26][27][28][29][30][31] Moreover, large retrospective analyses for drug safety and efficacy trials of statins in coronary artery disease have shown, that not only are these agents able to reduce cardiac disease-related mortality, but cancer incidence is also reduced by 28-33%. 32,33 These data further suggest these agents may have a role in cancer prophylaxis as well as therapy.…”

Section: Figurementioning

confidence: 99%

HMG-CoA reductase inhibitors and the malignant cell: the statin family of drugs as triggers of tumor-specific apoptosis

et al. 2002

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The statin family of drugs target HMG-CoA reductase, the ratelimiting enzyme of the mevalonate pathway, and have been used successfully in the treatment of hypercholesterolemia for the past 15 years. Experimental evidence suggests this key biochemical pathway holds an important role in the carcinogenic process. Moreover, statin administration in vivo can provide an oncoprotective effect. Indeed, in vitro studies have shown the statins can trigger cells of certain tumor types, such as acute myelogenous leukemia, to undergo apoptosis in a sensitive and specific manner. Mechanistic studies show bcl-2 expression is down-regulated in transformed cells undergoing apoptosis in response to statin exposure. In addition, the apoptotic response is in part due to the depletion of the downstream product geranylgeranyl pyrophosphate, but not farnesyl pyrophosphate or other products of the mevalonate pathway including cholesterol. Clinically, preliminary phase I clinical trials have shown the achievable plasma concentration corresponds to the dose range that can trigger apoptosis of tumor types in vitro. Moreover, little toxicity was evident in vivo even at high concentrations. Clearly, additional clinical trials are warranted to further assess the safety and efficacy of statins as novel and immediately available anti-cancer agents. In this article, the experimental evidence supporting a role for the statin family of drugs to this new application will be reviewed.

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Importance of mevalonate‐derived products in the control of HMG‐CoA reductase activity and growth of human lung adenocarcinoma cell line a549

Cited by 73 publications

References 29 publications

Survivin Down-regulation Plays a Crucial Role in 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Inhibitor-induced Apoptosis in Cancer

Survivin Down-regulation Plays a Crucial Role in 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Inhibitor-induced Apoptosis in Cancer

Chemical–Physical Changes in Cell Membrane Microdomains of Breast Cancer Cells After Omega-3 PUFA Incorporation

HMG-CoA reductase inhibitors and the malignant cell: the statin family of drugs as triggers of tumor-specific apoptosis

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