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Blood, 1 November 2003, Vol. 102, No. 9, pp. 3354-3362. Prepublished online as a Blood First Edition Paper on July 10, 2003; DOI 10.1182/blood-2003-03-0970. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-03-0970v1 102/9/3354    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 van de Donk, N. W. C. J. Articles by Bloem, A. C. Search for Related Content PubMed PubMed Citation Articles by van de Donk, N. W. C. J. Articles by Bloem, A. C. Related Collections Neoplasia Apoptosis Signal Transduction Gene Expression Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Inhibition of protein geranylgeranylation induces apoptosis in myeloma plasma cells by reducing Mcl-1 protein levels Niels W. C. J. van de Donk, Marloes M. J. Kamphuis, Berris van Kessel, Henk M. Lokhorst, and Andries C. Bloem From the Departments of Immunology and Hematology, University Medical Center Utrecht, The Netherlands. HMG-CoA reductase is the rate-limiting enzyme of the mevalonate pathway leading to the formation of cholesterol and isoprenoids such as farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP). The inhibition of HMG-CoA reductase by lovastatin induced apoptosis in plasma cell lines and tumor cells from patients with multiple myeloma. Here we show that cotreatment with mevalonate or geranylgeranyl moieties, but not farnesyl groups, rescued myeloma cells from lovastatin-induced apoptosis. In addition, the inhibition of geranylgeranylation by specific inhibition of geranylgeranyl transferase I (GGTase I) induced the apoptosis of myeloma cells. Apoptosis triggered by the inhibition of geranylgeranylation was associated with reduction of Mcl-1 protein expression, collapse of the mitochondrial transmembrane potential, expression of the mitochondrial membrane protein 7A6, cytochrome c release from mitochondria into the cytosol, and stimulation of caspase-3 activity. These results imply that protein geranylgeranylation is critical for regulating myeloma tumor cell survival, possibly through regulating Mcl-1 expression. Our results show that pharmacologic agents such as lovastatin or GGTase inhibitors may be useful in the treatment of multiple myeloma. 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