title: Statins inhibited the MIP-1α expression via inhibition of Ras/ERK and Ras/Akt pathways in myeloma cells.
abstract: Macrophage inflammatory protein-1alpha (MIP-1α) is detected at high concentrations in patients with multiple myeloma. It is thought to play an important role in the etiology of multiple myeloma and osteolysis. Thus, inhibiting MIP-1α expression may be useful in developing therapeutic treatments for multiple myeloma-induced osteolysis. In this study, we investigated the potential of statins to inhibit mRNA expression and secretion of MIP-1α in mouse myeloma cells (MOPC-31C). We found that statins inhibited the lipopolysaccharide (LPS)-induced MIP-1α mRNA expression and protein secretion in MOPC-31C cells. This inhibition was reversed when farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), intermediates of the mevalonate pathway, were combined with statins. Furthermore, statins reduced the GTP form of Ras, a phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2), and phosphorylated Akt. Our results indicate that statins inhibit biosynthesis of FPP and GGPP and thereby down regulate signal transduction of Ras/ERK and Ras/Akt pathways. The net effect suppresses LPS-induced MIP-1α mRNA expression and protein secretion in MOPC-31C cells. Thus, statins hold great promise for developing effective therapies against myeloma-induced osteolysis.
authors.affiliation: Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka, Japan.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Tsubaki
authors.affiliation: Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka, Japan; Department of Pharmacy, Japanese Red Cross Society Wakayama Medical Center, Wakayama, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Mashimo
authors.affiliation: Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Takeda
authors.affiliation: Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka, Japan.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Kino
authors.affiliation: Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka, Japan.
authors.forename: Arisa
authors.initials: A
authors.lastname: Fujita
authors.affiliation: Department of Food Science and Nutrition, Kinki University School of Agriculture, Nara, Nara, Japan.
authors.forename: Tatsuki
authors.initials: T
authors.lastname: Itoh
authors.affiliation: Department of Surgery and Kinki University School of Medicine, Osakasayama, Osaka, Japan.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Imano
authors.affiliation: Department of Pharmacy, Japanese Red Cross Society Wakayama Medical Center, Wakayama, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Sakaguchi
authors.affiliation: Department of Pathology, Kinki University School of Medicine, Osakasayama, Osaka, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Satou
authors.affiliation: Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka, Japan. Electronic address: nishida@phar.kindai.ac.jp.
authors.forename: Shozo
authors.initials: S
authors.lastname: Nishida
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D054405:Chemokine CCL3 / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D000077340:Fluvastatin; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D008070:Lipopolysaccharides; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D009101:Multiple Myeloma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D017368:Protein Prenylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D054405:Chemokine CCL3; D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D000077340:Fluvastatin; D019821:Simvastatin; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D018631:ras Proteins
keywords: MIP-1α; Myeloma; Ras; Statin