Molecular mechanism of the anti-cancer activity of cerivastatin, an inhibitor of HMG-CoA reductase, on aggressive human breast cancer cells

Denoyelle, Christophe; Albanese, Patricia; Uzan, Georges; Li, Hong; Vannier, Jean‐Pierre; Soria, Claudine

doi:10.1016/s0898-6568(02)00124-9

Cited by 110 publications

(92 citation statements)

References 52 publications

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“…Previous studies have shown that cholesterol-lowering drugs could inhibit Akt signaling in some cell types (16,17). Therefore, the effect of statins on the constitutive level of pAkt was examined in HepG2 cells.…”

Section: Pravastatin and Atorvastatin Decrease Pakt Levels And Inhibimentioning

confidence: 99%

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Statins induce mammalian target of rapamycin (mTOR)-mediated inhibition of Akt signaling and sensitize p53-deficient cells to cytostatic drugs

Roudier

Mistafa

Stenius

2006

Molecular Cancer Therapeutics

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Cholesterol-lowering statins have been shown to have anticancer effects in different models and sensitize human tumor cells to cytostatic drugs. We have investigated the effect of statins on Akt/protein kinase B signaling and the sensitizing effect of cytostatic drugs. It was found that insulin -and cytostatic drug -induced Akt phosphorylation and nuclear translocation was inhibited by pravastatin and atorvastatin in HepG2, A549, and H1299 cells in an mTOR-dependent manner. Statins also induced mTORdependent phosphorylation of insulin receptor substrate 1. In p53 wild-type cells (HepG2 and A549), pretreatment with statins did not sensitize cells to etoposide in concentrations which induced p53 stabilization. In line with our previous data, statins were found to attenuate the etoposide-induced p53 response. However, silencing p53 by RNA interference rescued the sensitizing effect. We also show that in a p53-deficient cell line (H1299), pretreatment with atorvastatin sensitized cells to etoposide, doxorubicin, and 5-fluorouracil and increased the level of apoptosis. Taken together, these data suggest that a mTOR-dependent, statin-induced inhibition of Akt phosphorylation and nuclear translocation sensitizes cells to cytostatic drugs. However, this effect can be counteracted in p53 competent cells by the ability of statins to destabilize p53. [Mol Cancer Ther 2006;5(11):2706 -15]

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Section: Pravastatin and Atorvastatin Decrease Pakt Levels And Inhibimentioning

confidence: 99%

“…For example, in breast cancer cells overexpressing Akt, cerivastatin decreased the levels of pAkt (17). Another recent study showed that simvastatin could inhibit the activation of Akt in small cell lung cancer cells (5).…”

Section: Introductionmentioning

confidence: 99%

Statins induce mammalian target of rapamycin (mTOR)-mediated inhibition of Akt signaling and sensitize p53-deficient cells to cytostatic drugs

Roudier

Mistafa

Stenius

2006

Molecular Cancer Therapeutics

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“…After different incubation times with ZOL, separation of particulate and cytosolic fractions was performed as previously described (Denoyelle et al, 2003). Briefly, MDA-MB-231 cells were washed with cold PBS, lysed in ice-cold buffer that contained phosphatase and protease inhibitors and centrifuged at 100 000 g for 30 min at 41C.…”

Section: Separation Of Particulate and Cytosolic Fractionsmentioning

confidence: 99%

“…In the same way, cells transformed by the activated RhoA gene (del Peso et al, 1997) or cells expressing a constitutively active form of RhoA (Yoshioka et al, 1998) have greatly promoted invasive ability, contributing to the acquisition of a metastatic phenotype in vivo. Finally, we recently demonstrated that RhoA activation contributes to breast cancer cell aggressivity (Denoyelle et al, 2003). Therefore, it would be interesting to determine whether the anticancer action of N-BPs could be related to the inhibition of Ras and/or RhoA prenylation, following the decrease of FPP and/or GGPP synthesis.…”

mentioning

confidence: 99%

New insights into the actions of bisphosphonate zoledronic acid in breast cancer cells by dual RhoA-dependent and -independent effects

Denoyelle¹,

Li²,

Jp³

et al. 2003

Br J Cancer

146

110

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Zoledronic acid (ZOL) is a nitrogen-containing bisphosphonate and its use in reducing osteoporosis and cancer-induced osteolysis is increasing. Recent findings indicated that ZOL has a direct effect on cancer cells. In this study, the effect of ZOL was examined on the aggressive MDA-MB-231 breast cancer cell line. ZOL induces an important inhibition of cell invasion at low concentrations (1 mM). This is not explained by modifications of proteases involved in cell invasiveness (matrix metalloproteinases and urokinase-type plasminogen activator), but by a disorganisation of actin cytoskeleton due to RhoA inhibition related to its defective prenylation as it was reversed by geranylgeraniol (GGOH) and mimicked by the Rho selective inhibitor C3 exoenzyme. In addition, ZOL inhibits the chemotactic effect induced by stromal cell-derived factor 1(SDF-1), a chemokine greatly involved in cancer metastasis to bone. This effect is related to both reduction of cell motility induced by RhoA inhibition and to a decreased expression of CXCR-4, the SDF-1 receptor. Finally, ZOL reduces Cox-2 expression and, consequently, the secretion of prostaglandins E2 (PGE2) in a RhoAindependent manner. This inhibition could contribute to bone protection in breast cancers because PGE2 stimulates osteoclastmediated bone resorption. In summary, new insights in the mechanism of ZOL action on aggressive breast cancer cells are demonstrated and could explain its beneficial action in both the reduction of osteolysis and prevention of metastasis.

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“…While initially developed for cholesterol reduction, statins and FTIs are now being used in the treatment of cancer. Here, they act by inhibition of protein prenylation of RhoA, resulting in the subsequent disruption of RhoA-dependant cell signalling, including the suppression of RhoA/ ROCK regulation of the actin cytoskeleton and the RhoA/FAK/AKT regulation of cell proliferation and invasive capacity (Denoyelle et al, 2003). This results in decreased cell proliferation, motility and invasiveness.…”

Section: Wt1 Represses Mevalonate Genes Fk Rae Et Almentioning

confidence: 99%

Anlaysis of complementary expression profiles following WT1 induction versus repression reveals the cholesterol/fatty acid synthetic pathways as a possible major target of WT1

et al. 2004

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Molecular mechanism of the anti-cancer activity of cerivastatin, an inhibitor of HMG-CoA reductase, on aggressive human breast cancer cells

Cited by 110 publications

References 52 publications

Statins induce mammalian target of rapamycin (mTOR)-mediated inhibition of Akt signaling and sensitize p53-deficient cells to cytostatic drugs

Statins induce mammalian target of rapamycin (mTOR)-mediated inhibition of Akt signaling and sensitize p53-deficient cells to cytostatic drugs

New insights into the actions of bisphosphonate zoledronic acid in breast cancer cells by dual RhoA-dependent and -independent effects

Anlaysis of complementary expression profiles following WT1 induction versus repression reveals the cholesterol/fatty acid synthetic pathways as a possible major target of WT1

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