HMG‐CoA reductase inhibitor‐induced L6 myoblast cell death: involvement of the phosphatidylinositol 3‐kinase pathway

Nakagawa, Hiroto; Mutoh, Tatsuro; Kumano, Takanori; Kuriyama, Masaru

doi:10.1016/s0014-5793(98)01320-9

Cited by 34 publications

(22 citation statements)

References 38 publications

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“…In the present work, we show that lovastatin treatment leads to a clear reduction of the kinase activity of PI3‐K in neuroblasts. This result agrees with previous works on the apoptosis induced by other statins in non‐neuronal cell types (Nakagawa et al . 1998; Weiss et al .…”

Section: Discussionsupporting

confidence: 94%

Lovastatin inhibits the growth and survival pathway of phosphoinositide 3‐kinase/protein kinase B in immortalized rat brain neuroblasts

Cerezo-Guisado¹,

García‐Marín²,

Lorenzo³

et al. 2005

Journal of Neurochemistry

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We previously showed that lovastatin, an HMG-CoA reductase inhibitor, suppresses cell growth by inducing apoptosis in rat brain neuroblasts. Our aim was to study intracellular signalling induced by lovastatin in neuroblasts. Lovastatin significantly decreases the phosphoinositide 3-kinase (PI3-K) activity in a concentration-dependent manner. Expression of p85 subunit and its association with phosphotyrosine-containing proteins are unaffected by lovastatin. Lovastatin decreases protein kinase B (PKB)/Akt phosphorylation, and its downstream effectors, p70 S6K and the eukaryotic initiation factor 4E (eIF4E) regulatory protein 1, 4E-BP1, in a concentration-dependent manner, and reduces p70 S6K expression.Lovastatin effects are fully prevented with mevalonate. Only the highest dose of PI3-K inhibitors that significantly reduce PI3-K kinase activity induces apoptosis in neuroblasts but to a lower degree than lovastatin. In summary, this work shows that treatment of brain neuroblasts with lovastatin leads to an inhibition of the main pathway that controls cell growth and survival, PI3-K/PKB and the subsequent blockade of downstream proteins implicated in the regulation of protein synthesis. This work suggests that inactivation of the antiapoptotic PI3-K appears insufficient to induce the degree of neuroblasts apoptosis provoked by lovastatin, which must necessarily involve other intracellular pathways. These findings might contribute to elucidate the molecular mechanisms of some statins effects in the central nervous system. Keywords: apoptosis, lovastatin, neuroblasts, phosphoinositide 3-kinase, phosphorylation, protein kinase B/Akt. It is well established that mevalonate pathway, which yields different isoprenoid compounds and cholesterol, plays an important role in cell growth and survival (Goldstein and Brown 1990). Mevalonate is intracellularly synthesized from 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA), and this process is catalyzed by HMG-CoA reductase, the ratelimiting enzyme in this pathway (Goldstein and Brown 1990). Several studies show that competitive inhibitors of HMG-CoA reductase (statins), such as lovastatin, simvastatin and pravastatin, not only block the biosynthesis of mevalonate but, in addition, inhibit the growth and proliferation of both normal and tumour cells (Falke et al. 1989;Jones et al. 1994;Raiteri et al. 1997). Furthermore, inhibition of HMG-CoA reductase is also known to induce cell death by apoptosis in different non-neuronal cell types (Jones et al. 1994;Perez-Sala and Mollinedo 1994;Padayatty et al. 1997;Guijarro et al. 1998).This metabolic pathway is essential during late fetal and early neonatal life to ensure normal growth and development of the brain (Cavender et al. 1995;Spady and Dietschy 1983). Several studies suggest that HMG-CoA reductase inhibitors could seriously affect cholesterol Received April 13, 2005; accepted April 27, 2005. Address correspondence and reprint requests to Maria Julia Bragado, Departamento de Bioquímica, Biología Molecular y Genética, Fa...

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Section: Discussionsupporting

confidence: 94%

Lovastatin inhibits the growth and survival pathway of phosphoinositide 3‐kinase/protein kinase B in immortalized rat brain neuroblasts

Cerezo-Guisado¹,

García‐Marín²,

Lorenzo³

et al. 2005

Journal of Neurochemistry

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“…Since mevalonate is an upstream intermediate in the synthesis of reactive farnesyl residues, synergistic suppression of HMGCoA reductase activity by the combined treatment of statins and c-tocotrienol might ultimately prevent the farnesylation and anchoring of Ras to the interior of the cell membrane [41,42]. Once Ras is anchored to the cell membrane, it is able to interact with activated membrane bound receptors, such as the EGFreceptor, and initiate activation of the MAPK and Akt mitogenic signaling pathways [41][42][43][44]. Therefore, the synergistic antiproliferative effects of combined statin and c-tocotrienol treatment may result from their independent actions to inhibit HMGCoA reductase activity, mevalonate synthesis, and subsequent farnesylation of second messengers involved in mediating EGF-dependent mitogenic signaling.…”

Section: Discussionmentioning

confidence: 99%

Synergistic Antiproliferative Effects of γ‐Tocotrienol and Statin Treatment on Mammary Tumor Cells

Wali

Sylvester

2007

Lipids

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Statins are potent inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMGCoA) reductase and display anticancer activity, but their clinical use is limited by their high-dose toxicity. Similarly, gamma-tocotrienol, an isoform of vitamin E, also reduces HMGCoA reductase activity and displays potent anticancer activity. Studies were conducted to determine if combined low dose treatment of gamma-tocotrienol with individual statins resulted in a synergistic antiproliferative effect on neoplastic mouse +SA mammary epithelial cells. Treatment with 3-4 microM gamma-tocotrienol or 2-8 microM simvastatin, lovastatin or mevastatin alone resulted in a significant decrease, whereas treatment with 10-100 microM pravastatin had no effect on +SA cell growth. However, combined treatment of subeffective doses (0.25 or 10 microM) of individual statins with 0.25-2.0 microM gamma-tocotrienol resulted in a dose-responsive synergistic inhibition in +SA cell proliferation. Additional studies showed that treatment with subeffective doses of individual statins or gamma-tocotrienol alone had no effect, whereas combined treatment of these compounds resulted in a relatively large decrease in intracellular levels of phosphorylated (activated) MAPK, JNK, p38, and Akt. These findings strongly suggest that combined low dose treatment of gamma-tocotrienol with individual statins may have potential value in the treatment of breast cancer without causing myotoxicity that is associated with high dose statin treatment.

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“…Potent inhibitors of PI3K, including LY294002 and the hydroxymethylglutaryl coenzyme A inhibitor simvastatin, have been reported to directly decrease viability of L6 myoblasts (19). In contrast to LY294002, dexamethasone pretreatment only partially inhibits Akt phosphorylation by IGF-I.…”

Section: Discussionmentioning

confidence: 99%

Dexamethasone Inhibits Insulin-Like Growth Factor Signaling and Potentiates Myoblast Apoptosis

2000

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In the critically ill, glucocorticoids induce myopathy, combining profound protein catabolism and mild myotubular death. Insulin-like growth factors (IGFs) inhibit muscle catabolism through activation of phosphatidylinositol 3-kinase (PI3K). Using rat L6 myoblasts, we show that IGF-I also acts through PI3K to inhibit apoptosis induced by hyperosmolar metabolic stress with 300 mM mannitol. We find that the glucocorticoid dexamethasone inhibits this antiapoptotic effect of IGF-I by impairing PI3K signaling. Dexamethasone induces overexpression of the PI3K subunit p85alpha, which, in turn, competes with the complete PI3K heterodimer for binding at insulin receptor substrate-1, inhibiting PI3K activation. Dexamethasone blocks IGF-I-induced phosphorylation of Akt, a PI3K-dependent process. Increased cellular p85alpha abundance, induced by either 10 microM dexamethasone or transient transfection with a plasmid coding for p85alpha, significantly inhibits IGF-I rescue from apoptosis induced by mannitol, as indicated by both loss of cell viability and increased activity of caspase-3 by fluorogenic assay. Conversely, constitutively active PI3K inhibits death induced by mannitol, even in the presence of dexamethasone. These findings may have particular relevance in the pathogenesis of acute steroid myopathy in critical illness, in which catabolic glucocorticoid effects combine with acute metabolic stressors, including sepsis, fasting, and chemical denervation.

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HMG‐CoA reductase inhibitor‐induced L6 myoblast cell death: involvement of the phosphatidylinositol 3‐kinase pathway

Cited by 34 publications

References 38 publications

Lovastatin inhibits the growth and survival pathway of phosphoinositide 3‐kinase/protein kinase B in immortalized rat brain neuroblasts

Lovastatin inhibits the growth and survival pathway of phosphoinositide 3‐kinase/protein kinase B in immortalized rat brain neuroblasts

Synergistic Antiproliferative Effects of γ‐Tocotrienol and Statin Treatment on Mammary Tumor Cells

Dexamethasone Inhibits Insulin-Like Growth Factor Signaling and Potentiates Myoblast Apoptosis

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