title: Bisphosphonates and statins inhibit expression and secretion of MIP-1α via suppression of Ras/MEK/ERK/AML-1A and Ras/PI3K/Akt/AML-1A pathways.
abstract: Osteolytic bone disease in multiple myeloma (MM) is associated with upregulated osteoclast activity. Macrophage inflammatory protein-1α (MIP-1α) is crucially involved in the development of osteolytic bone lesions in MM. We previously reported that minodronate inhibited lipopolysaccharide-induced MIP-1α secretion in mouse myeloma cells. However, it remains unknown whether bisphosphonates and statins inhibit MIP-1α secretion by human MM cells. In present study, we investigated whether bisphosphonates and statins had any inhibitory effect on MIP-1α secretion by human myeloma cells and the mechanism underlying this effect. In this study, we found that bisphosphonates and statins inhibited MIP-1α mRNA and MIP-1α secretion and suppressed extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt phosphorylation by inhibiting Ras prenylation. Moreover, bisphosphonates and statins suppressed the expression of acute myeloid leukemia-1A (AML-1A) mRNA, a MIP-1α transcription factor. These results indicate that bisphosphonates and statins suppress the Ras/mitogen-activated protein kinase kinase/ERK/AML-1A and Ras/phosphatidylinositol-3 kinase/Akt/AML-1A pathways, thereby inhibiting MIP-1α secretion by MM cells. Therefore, use of MIP-1α expression inhibitors such as bisphosphonates and statins may provide a new therapeutic approach to inhibiting tumour progression and bone destruction in MM patients.
authors: Division of Pharmacotherapy, Kinki University School of Pharmacy Kowakae, Higashi-Osaka, Japan.
authors: Masanobu
authors: M
authors: Tsubaki
authors: Division of Pharmacotherapy, Kinki University School of Pharmacy Kowakae, Higashi-Osaka, Japan.
authors: Tomoya
authors: T
authors: Takeda
authors: Division of Pharmacotherapy, Kinki University School of Pharmacy Kowakae, Higashi-Osaka, Japan.
authors: Kotaro
authors: K
authors: Sakamoto
authors: Division of Pharmacotherapy, Kinki University School of Pharmacy Kowakae, Higashi-Osaka, Japan.
authors: Hirotaka
authors: H
authors: Shimaoka
authors: Division of Pharmacotherapy, Kinki University School of Pharmacy Kowakae, Higashi-Osaka, Japan.
authors: Arisa
authors: A
authors: Fujita
authors: Department of Food Science and Nutrition, Kinki University School of Agriculture Nara, Nara, Japan.
authors: Tatsuki
authors: T
authors: Itoh
authors: Department of Surgery, Kinki University School of Medicine Osakasayama, Osaka, Japan.
authors: Motohiro
authors: M
authors: Imano
authors: 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: Kenji
authors: K
authors: Mashimo
authors: 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: Daiichiro
authors: D
authors: Fujiwara
authors: Department of Pharmacy, Japanese Red Cross Society Wakayama Medical Center Wakayama, Japan.
authors: Katsuhiko
authors: K
authors: Sakaguchi
authors: Department of Pathology, Kinki University School of Medicine Osakasayama, Osaka, Japan.
authors: Takao
authors: T
authors: Satou
authors: Division of Pharmacotherapy, Kinki University School of Pharmacy Kowakae, Higashi-Osaka, Japan.
authors: Shozo
authors: S
authors: Nishida
keywords: AML-1A; Akt; Bisphosphonate; ERK; MIP-1α; Ras; myeloma; statin
references: Cancer Sci. 2008 Jan;99(1):152-8
references: 17979996
references: Mol Cell Endocrinol. 2012 Sep 25;361(1-2):219-31
references: 22579611
references: Blood. 2003 May 15;101(10):3778-83
references: 12560229
references: Cancer. 1997 Oct 15;80(8 Suppl):1557-63
references: 9362422
references: Eur J Haematol. 2010 Feb 1;84(2):137-44
references: 19878271
references: Mol Cell Biochem. 2005 Jan;269(1-2):109-14
references: 15786722
references: J Exp Clin Cancer Res. 2011 Aug 10;30:74
references: 21831290
references: J Leukoc Biol. 1998 Oct;64(4):528-36
references: 9766634
references: Br J Haematol. 2003 Jan;120(1):53-5
references: 12492576
references: Oncogene. 2002 Feb 21;21(9):1346-58
references: 11857078
references: Life Sci. 2003 Oct 10;73(21):2655-64
references: 13679234
references: Semin Hematol. 2001 Jul;38(3):276-85
references: 11486316
references: Blood. 2006 Nov 15;108(10):3465-71
references: 16849642
references: Leuk Lymphoma. 1994 Jul;14(3-4):335-40
references: 7950924
references: Blood. 2001 Jun 1;97(11):3349-53
references: 11369623
references: Endocr Rev. 1998 Feb;19(1):80-100
references: 9494781
references: Blood. 2002 Sep 15;100(6):2195-202
references: 12200385
references: Biochem Pharmacol. 2013 Jan 15;85(2):163-72
references: 23085435
references: Blood. 2000 Jul 15;96(2):671-5
references: 10887133
references: Blood. 2003 May 1;101(9):3568-73
references: 12506012
references: J Clin Invest. 2001 Dec;108(12):1833-41
references: 11748267
references: Exp Hematol. 2005 Mar;33(3):272-8
references: 15730850
references: Semin Oncol. 1999 Oct;26(5 Suppl 13):10-22
references: 10528890
references: Carcinogenesis. 2005 May;26(5):883-91
references: 15705602
references: J Cell Physiol. 2000 May;183(2):196-207
references: 10737895
references: J Bone Miner Res. 2000 Apr;15(4):650-62
references: 10780857
references: Drug Resist Updat. 2008 Jun;11(3):63-76
references: 18440854
references: Mol Cell Biochem. 2007 Oct;304(1-2):53-60
references: 17549607
references: Stem Cells. 1995 Aug;13 Suppl 2:1-9
references: 8520495
references: J Leukoc Biol. 2004 Jun;75(6):1147-55
references: 14982949
references: Endocr Relat Cancer. 2006 Mar;13(1):7-26
references: 16601276
references: J Cell Biochem. 2010 Dec 15;111(6):1661-72
references: 21053363
references: Blood. 2004 Mar 15;103(6):2308-15
references: 14615378