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Prepublished online as a Blood First Edition Paper on July 10, 2003; DOI 10.1182/blood-2003-03-0970. This Article 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 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 Social Bookmarking                   What's this? Submitted March 28, 2003 Accepted June 26, 2003 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* Department of Immunology, University Medical Center Utrecht, Utrecht, The Netherlands Department of Hematology, University Medical Center Utrecht, Utrecht, The Netherlands * Corresponding author; email: a.bloem{at}azu.nl. HMG-CoA reductase is the rate-limiting enzyme of the mevalonate pathway leading to the formation of cholesterol and isoprenoids like farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP). 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 co-treatment with mevalonate or geranylgeranyl moieties, but not farnesyl groups, rescued myeloma cells from lovastatin-induced apoptosis. Also inhibition of geranylgeranylation by specific inhibition of geranylgeranyl transferase I (GGTase I) resulted in induction of apoptosis of myeloma cells. Apoptosis triggered by 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 the regulation of myeloma tumor cell survival, possibly through the regulation of Mcl-1 expression. Our results show that pharmacological agents such as lovastatin or GGTase inhibitors may be useful in the treatment of multiple myeloma. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S.-i. Kagami, T. Owada, H. Kanari, Y. Saito, A. Suto, K. Ikeda, K. Hirose, N. 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