Inhibition of Protein Geranylgeranylation and RhoA/RhoA Kinase Pathway Induces Apoptosis in Human Endothelial Cells

Li, Xianwu; Liu, Li; Tupper, Joan C.; Bannerman, Douglas D.; Winn, Robert K.; Sebti, Saı̈d M.; Hamilton, Andrew D.; Harlan, John M.

doi:10.1074/jbc.m201253200

Cited by 173 publications

(154 citation statements)

References 51 publications

(66 reference statements)

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“…Notably, we found that osteosarcoma cell death induced by lipophilic statins is a caspase-dependent apoptotic process, which is consistent with recent studies in non osseous cells. 28,29 Since we found that statins activated caspase-9 and -3-like activity, but not caspase-8 activity, in a time-dependent manner, we conclude that lipophilic statins induce apoptosis in human osteosarcoma cells mostly through activation of the mitochondrial apoptotic pathway. or the solvent, the expression of Bcl-2, Bax and IAP/survivin was evaluated by semiquantitative RT-PCR analysis and the results expressed as treated over control ratio after correction for the housekeeping gene GAPDH.…”

Section: Discussionmentioning

confidence: 71%

“…Our finding that restoration of RhoA activity abolished the inhibition of Bcl-2 and prevented cell death induced by statins indicates that Bcl-2 plays an essential role in protecting osteosarcoma cells from apoptosis induced by RhoA inactivation. Although a link between MAPKs, Bcl-2 and Mcl-1 has been reported in some other cell types, 24,25 and RhoA inhibition has been linked to Bcl-2 downregulation in the induction of apoptosis by statins in some cancer cells, 28,34,38 evidence implicating these molecules in the mechanisms of action of statins in human osteosarcoma cells was lacking. The present results point to a direct implication of p42/p44-MAPKs signaling downstream of RhoA as a mediator of the effects of statins on Bcl-2 and apoptosis in osteosarcoma cells.…”

Section: Discussionmentioning

confidence: 99%

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RhoA GTPase inactivation by statins induces osteosarcoma cell apoptosis by inhibiting p42/p44-MAPKs-Bcl-2 signaling independently of BMP-2 and cell differentiation

et al. 2006

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Osteosarcoma is the most common primary bone tumour in young adults. Despite improved prognosis, resistance to chemotherapy remains responsible for failure of osteosarcoma treatment. The identification of signals that promote apoptosis may provide clues to develop new therapeutic strategies for chemoresistant osteosarcoma. Here, we show that lipophilic statins (atorvastatin, simvastatin, cerivastatin) markedly induce caspases-dependent apoptosis in various human osteosarcoma cells, independently of bone morphogenetic protein (BMP)-2 signaling and cell differentiation. Although statins increased BMP-2 expression, the proapoptotic effect of statins was not prevented by the BMP antagonist noggin, and was abolished by mevalonate and geranylgeranylpyrophosphate, suggesting the involvement of defective protein geranylgeranylation. Consistently, lipophilic statins induced membrane RhoA relocalization to the cytosol and inhibited RhoA activity, which resulted in decreased phospho-p42/p44-mitogen-activated protein kinases (MAPKs) and Bcl-2 levels. Constitutively active RhoA rescued phospho-p42/p44-MAPKs and Bcl-2 and abolished statininduced apoptosis. Thus, lipophilic statins induce caspasedependent osteosarcoma cell apoptosis by a RhoA-p42/p44 MAPKs-Bcl-2-mediated mechanism, independently of BMP-2 signaling and cell differentiation.

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Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 99%

RhoA GTPase inactivation by statins induces osteosarcoma cell apoptosis by inhibiting p42/p44-MAPKs-Bcl-2 signaling independently of BMP-2 and cell differentiation

et al. 2006

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“…26 Mevastatin, for example, inhibits bone resorption and induces osteoclast apoptosis in vitro by inhibition of protein prenylation. 27 Furthermore, statins have been shown to induce apoptosis in melanoma, 28 thyroid cancer, [29][30] colon carcinoma, 32,33 squamous cell carcinoma, 34 breast cancer, 35 acute myeloid leukemia, 36 malignant lymphoma, 37 and multiple myeloma cells 14,38 in vitro. In our experiments, statins have been used in much lower concentrations than in most in vitro studies published with complete reversal of CAM-DR, suggesting realistically achievable doses in humans.…”

Section: Discussionmentioning

confidence: 99%

The HMG-CoA reductase inhibitor simvastatin overcomes cell adhesion–mediated drug resistance in multiple myeloma by geranylgeranylation of Rho protein and activation of Rho kinase

Schmidmaier¹,

Baumann²,

Simsek³

et al. 2004

Blood

106

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Primary drug resistance is a major problem in multiple myeloma, an incurable disease of the bone marrow. Cell adhesion-mediated drug resistance (CAM-DR) causes strong primary resistance. By coculturing multiple myeloma cells with bone marrow stromal cells (BMSCs), we observed a CAM-DR of about 50% to melphalan, treosulfan, doxorubicin, dexamethasone, and bortezomib, which was not reversed by secreted soluble factors. Targeting the adhesion molecules lymphocyte function-associated antigen 1 (LFA-1) and very late antigen 4 (VLA-4) by monoclonal antibodies or by the LFA-1 inhibitor LFA703 reduced CAM-DR significantly. Only statins such as simvastatin and lovastatin, however, were able to completely restore chemosensitivity. All these effects were not mediated by deadhesion or reduced secretion of interleukin 6. Targeting

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“…Inhibition of Rho or ROCK results in activation of caspases 3, 8 and 9, and glioma cell apoptosis [110]. Treatment of human umbilical vein endothelial cells with ROCK inhibitors Y-27632 and HA-1077 causes dose-dependent cell death, which is dependent on de novo protein synthesis and is associated with an increase in p53 protein level [76].…”

Section: In Vitro Evidencementioning

confidence: 99%

Rho kinase in the regulation of cell death and survival

Shi

Wei

2007

Arch. Immunol. Ther. Exp.

211

181

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SummaryRho kinase (ROCK) belongs to a family of serine/threonine kinases that are activated via interaction with Rho GTPases. ROCK is involved in a wide range of fundamental cellular functions such as contraction, adhesion, migration, and proliferation. Recent studies have shown that ROCK plays an important role in the regulation of apoptosis in various cell types and animal disease models. Two ROCK isoforms, ROCK1 and ROCK2, are assumed to be function redundant, based largely on kinase construct overexpression, and chemical inhibitors (Y27632 and fasudil), which inhibit both ROCK1 and ROCK2. Gene targeting and RNA interference approaches allow further dissection of distinct cellular, physiological and patho-physiological functions of the two ROCK isoforms. This review, based on recent molecular, cellular and animal studies, focuses on the current understanding of ROCK signaling in the regulation of apoptosis and highlights the new findings from recently generated ROCK-deficient mice.

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Inhibition of Protein Geranylgeranylation and RhoA/RhoA Kinase Pathway Induces Apoptosis in Human Endothelial Cells

Cited by 173 publications

References 51 publications

RhoA GTPase inactivation by statins induces osteosarcoma cell apoptosis by inhibiting p42/p44-MAPKs-Bcl-2 signaling independently of BMP-2 and cell differentiation

RhoA GTPase inactivation by statins induces osteosarcoma cell apoptosis by inhibiting p42/p44-MAPKs-Bcl-2 signaling independently of BMP-2 and cell differentiation

The HMG-CoA reductase inhibitor simvastatin overcomes cell adhesion–mediated drug resistance in multiple myeloma by geranylgeranylation of Rho protein and activation of Rho kinase

Rho kinase in the regulation of cell death and survival

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