Inhibition of protein geranylgeranylation induces apoptosis in myeloma plasma cells by reducing Mcl-1 protein levels.
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.
van de Donk
Niels W C J
NW
Department of Immunology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
Kamphuis
Marloes M J
MM
van Kessel
Berris
B
Lokhorst
Henk M
HM
Bloem
Andries C
AC
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors; D017209:Apoptosis / Q000187:drug effects*; D001854:Bone Marrow Cells / Q000473:pathology; D045744:Cell Line, Tumor; D004224:Diterpenes / Q000494:pharmacology; D015536:Down-Regulation; D004336:Drug Antagonism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008148:Lovastatin / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects; D024101:Mitochondrial Proteins / Q000187:drug effects; D009101:Multiple Myeloma / Q000473:pathology*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000378:metabolism; D017368:Protein Prenylation / Q000187:drug effects* / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2; D014407:Tumor Cells, Cultured
D004224:Diterpenes; D004791:Enzyme Inhibitors; D024101:Mitochondrial Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D008148:Lovastatin; C017338:geranylgeraniol; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I