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Blood, 1 October 2007, Vol. 110, No. 7, pp. 2674-2684. Prepublished online as a Blood First Edition Paper on July 10, 2007; DOI 10.1182/blood-2006-09-048033. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2006-09-048033v1 110/7/2674    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Shachaf, C. M. Articles by Felsher, D. W. Search for Related Content PubMed PubMed Citation Articles by Shachaf, C. M. Articles by Felsher, D. W. Related Collections Oncogenes and Tumor Suppressors Signal Transduction Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Inhibition of HMGcoA reductase by atorvastatin prevents and reverses MYC-induced lymphomagenesis Catherine M. Shachaf1,2, Omar D. Perez2,3, Sawsan Youssef4, Alice C. Fan1, Sailaja Elchuri1, Matthew J. Goldstein4, Amy E. Shirer1, Orr Sharpe2, Joy Chen1, Dennis J. Mitchell2,3, Maria Chang1, Garry P. Nolan2,3, Lawrence Steinman4, and Dean W. Felsher1 1 Division of Medical Oncology, Departments of Medicine and Pathology, Stanford University; 2 Department of Microbiology & Immunology, Stanford University; 3 The Baxter Laboratory for Genetic Pharmacology, Stanford University; 4 Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA Statins are a class of drugs that inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMGcoA) reductase, a critical enzyme in the mevalonate pathway. Several reports document that statins may prevent different human cancers. However, whether or not statins can prevent cancer is controversial due to discordant results. One possible explanation for these conflicting conclusions is that only some tumors or specific statins may be effective. Here, we demonstrate in an in vivo transgenic model in which atorvastatin reverses and prevents the onset of MYC-induced lymphomagenesis, but fails to reverse or prevent tumorigenesis in the presence of constitutively activated K-Ras (G12D). Using phosphoprotein fluorescence-activated cell sorter (FACS) analysis, atorvastatin treatment was found to result in the inactivation of the Ras and ERK1/2 signaling pathways associated with the dephosphorylation and inactivation of MYC. Correspondingly, tumors with a constitutively activated K-Ras (G12D) did not exhibit dephosphorylation of ERK1/2 and MYC. Atorvastatin's effects on MYC were specific to the inhibition of HMGcoA reductase, as treatment with mevalonate, the product of HMG-CoA reductase activity, abrogated these effects and inhibited the ability of atorvastatin to reverse or suppress tumorigenesis. Also, RNAi directed at HMGcoA reductase was sufficient to abrogate the neoplastic properties of MYC-induced tumors. Thus, atorvastatin, by inhibiting HMGcoA reductase, induces changes in phosphoprotein signaling that in turn prevent MYC-induced lymphomagenesis. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: C. M. Shachaf, A. J. Gentles, S. Elchuri, D. Sahoo, Y. Soen, O. Sharpe, O. D. Perez, M. Chang, D. Mitchel, W. H. Robinson, et al. Genomic and Proteomic Analysis Reveals a Threshold Level of MYC Required for Tumor Maintenance Cancer Res., July 1, 2008; 68(13): 5132 - 5142. [Abstract] [Full Text] [PDF]

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