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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 (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 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. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted September 21, 2006 Accepted June 6, 2007 Inhibition of HMGcoA reductase by atorvastatin prevents and reverses MYC-induced lymphomagenesis Catherine M Shachaf, Omar D Perez, Sawsan Youssef, Alice C Fan, Sailaja Elchuri, Matthew J Goldstein, Amy E Shirer, Orr Sharpe, Joy Chen, Dennis J Mitchell, Maria Chang, Garry P Nolan, Lawrence Steinman, and Dean W. Felsher* Depts of Medicine & Pathology, Division of Medical Oncology, Stanford University, Stanford, CA Baxter Laboratory for Genetic Pharmacology, Stanford University, Stanford, CA Dept of Neurology & Neurological Sciences, Stanford University, Stanford, CA Dept of Microbiology & Immunology, Stanford University, Stanford, CA * Corresponding author; email: dfelsher{at}stanford.edu. 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 that 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). Utilizing phospho-protein 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 HMG-CoA reductase, as treatment with mevalonate 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 phospho-protein 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: T. S. Gujral and G. MacBeath Emerging Miniaturized Proteomic Technologies to Study Cell Signaling in Clinical Samples Sci. Signal., October 20, 2009; 2(93): pe65 - pe65. [Abstract] [Full Text] [PDF] 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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