Ras CAAX Peptidomimetic FTI-277 Selectively Blocks Oncogenic Ras Signaling by Inducing Cytoplasmic Accumulation of Inactive Ras-Raf Complexes

Lerner, Edwina C.; Qian, Yimin; Blaskovich, Michelle A.; Fossum, Renae D.; Vogt, Andreas; Sun, Jiazhi; Cox, Adrienne D.; Der, Channing J.; Hamilton, Andrew D.; Sebti, Saı̈d M.

doi:10.1074/jbc.270.45.26802

Cited by 342 publications

(275 citation statements)

References 37 publications

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“…The speci®city of PD 98059 for inhibiting the ERK-speci®c activator, MEK, has been described previously (Alessi et al, 1995). We demonstrated previously that FTI-277 (provided by S Sebti and A Hamilton) can potently inhibit farnesyltransferase in vitro (IC 50 =500 pM) and is highly selective for farnesyltransferase over geranylgeranyltransferase I in vitro (IC 50 =50 mM) and in vivo (Lerner et al, 1995).…”

Section: Molecular Constructsmentioning

confidence: 65%

Ras, but not Src, transformation of RIE-1 epithelial cells is dependent on activation of the mitogen-activated protein kinase cascade

et al. 1998

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Src transformation of NIH3T3 mouse ®broblasts has been shown to be dependent on Ras function. Since we recently showed that the signaling pathways that mediate Ras transformation of RIE-1 rat intestinal epithelial cells are distinct from those that cause Ras transformation of ®broblasts, we utilized three approaches to determine if Src transformation of RIE-1 cells is dependent on Ras. First, although both Ras and Src cause upregulation of an epidermal growth factor (EGF) receptor-dependent autocrine growth loop, only Ras transformation required this activity. Second, whereas both Src and Ras caused upregulation of the p42 and p44 mitogen-activated protein kinases (MAPKs), only Ras transformation was blocked by the inhibition of MAPK activation by treatment with the PD 98059 MEK inhibitor. Third, treatment with the farnesyltransferase inhibitor FTI-277 blocked Ras, but not Src, transformation. Taken together, these observations suggest that Src transformation of RIE-1 cells is not dependent on Ras. Finally, we determined that Ras activation of Raf-independent pathways alone is su cient to cause growth transformation of RIE-1 cells. Thus, both Ras and Src cause transformation of RIE-1 cells via pathways distinct from those required to cause transformation of NIH3T3 cells.

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Section: Molecular Constructsmentioning

confidence: 65%

Ras, but not Src, transformation of RIE-1 epithelial cells is dependent on activation of the mitogen-activated protein kinase cascade

et al. 1998

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“…To test this hypothesis further, the effect of FTI-277 and GGTI-298 that potently and selectively inhibit FTase and GGTase, respectively, was compared with the action of ZOL on MDA-MB-231 cell invasiveness. These inhibitors have been widely used to identify the prenylated proteins involved in the biological functions of various cell types (Lerner et al, 1995;Vogt et al, 1996). The incubation of MDA-MB-231 cells with GGTI-298 mimicked the anti-invasive effect of ZOL, whereas FTI-277 was devoid of effect.…”

Section: Discussionmentioning

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

147

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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“…Inhibition of the ®rst of these steps (farnesylation of the cysteine residue of the C-terminal CAAX motif) results in the accumulation of Ras-Raf complexes in the cytosol which are not able to interact with the signalling machinery at the cell surface (Lerner et al, 1995a;Miyake et al, 1996). Although originally conceived for tumours harbouring oncogenic mutations of Ras, we hypothesized that FTIs would also be of use in human tumours such as astrocytomas, in which Ras is functionally activated though otherwise normal.…”

Section: Discussionmentioning

confidence: 99%

Growth inhibition of astrocytoma cells by farnesyl transferase inhibitors is mediated by a combination of anti-proliferative, pro-apoptotic and anti-angiogenic effects

1999

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While 25% of human cancers harbor oncogenic Ras mutations, such mutations are not found in astrocytomas. We have previously demonstrated that the activation of receptor tyrosine kinases expressed by malignant human astrocytoma cells and specimens results in functional upregulation of the Ras signalling pathway and increased levels of activated Ras.GTP. Farnesyl transferase inhibitors (FTIs) are promising anti-cancer agents in early clinical trials, which may exert their e ect through pharmacological inhibition of the Ras signalling pathway. In this study we establish the anti-tumorigenic properties of the FTI L-744,832 against a panel of malignant human astrocytoma cell lines. Furthermore, we demonstrate the multiple mechanisms by which L-744,832 exerts its e ect. L-744,832 demonstrates both cytostatic and cytotoxic e ects on astrocytoma cells, and cells expressing a truncated constitutively phosphorylated Epidermal Growth Factor Receptor common in highgrade astrocytomas (EGFRvIII/p140 EGF-R ) demonstrate increased sensitivity to the agent. L-744,832 is capable of inducing apoptosis in astrocytoma cells under anchoragedependent conditions; this process occurs in a p53-independent manner and is associated with increased expression of Bax and Bak. L-744,832 also induces cell cycle arrest at both the G 1 /M and G 2 /S checkpoints; this process is also independent of p53 mutational status. Cell cycle arrest in drug-treated cells can be accompanied by induction of p21 WAF1/CIP1 , but this induction is not necessary for the cell cycle inhibitory e ects, nor is it dependent on functional p53. Finally, angiogenesis in astrocytomas has been shown to be dependent on secretion of Vascular Endothelial Growth Factor (VEGF) by tumour cells, particularly under hypoxic conditions. L-744,832 potently inhibits the secretion of VEGF under hypoxic conditions. These combinations of mechanisms suggest that these tumours, despite the absence of oncogenic Ras mutations, will be amenable to growth inhibition by FTIs, through a combination of anti-proliferative, pro-apoptotic, and anti-angiogenic e ects.

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Ras CAAX Peptidomimetic FTI-277 Selectively Blocks Oncogenic Ras Signaling by Inducing Cytoplasmic Accumulation of Inactive Ras-Raf Complexes

Abstract: Ras-induced malignant transformation requiresRas proteins are plasma membrane-associated GTPases that function as relay switches transducing biological information from extracellular signals to the nucleus (for review, see Refs.

Cited by 342 publications

References 37 publications

Ras, but not Src, transformation of RIE-1 epithelial cells is dependent on activation of the mitogen-activated protein kinase cascade

Ras, but not Src, transformation of RIE-1 epithelial cells is dependent on activation of the mitogen-activated protein kinase cascade

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

Growth inhibition of astrocytoma cells by farnesyl transferase inhibitors is mediated by a combination of anti-proliferative, pro-apoptotic and anti-angiogenic effects

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