Bisphosphonates and statins inhibit expression and secretion of MIP-1 alpha via suppression of Ras/MEK/ERK/AML-1A and Ras/PI3K/Akt/AML-1A pathways

作者：Tsubaki Masanobu; Takeda Tomoya; Sakamoto Kotaro; Shimaoka Hirotaka; Fujita Arisa; Itoh Tatsuki; Imano Motohiro; Mashimo Kenji; Fujiwara Daiichiro; Sakaguchi Katsuhiko; Satou Takao; Nishida Shozo^*

来源：American Journal of Cancer Research, 2015, 5(1): 168-179.

• Bisphosphonate
• statin
• MIP-1 alpha
• AML-1A
• myeloma
• Ras
• ERK
• Akt

Osteolytic bone disease in multiple myeloma (MM) is associated with upregulated osteoclast activity. Macrophage inflammatory protein-1 alpha (MIP-1 alpha) is crucially involved in the development of osteolytic bone lesions in MM. We previously reported that minodronate inhibited lipopolysaccharide-induced MIP-1 alpha secretion in mouse myeloma cells. However, it remains unknown whether bisphosphonates and statins inhibit MIP-1 alpha secretion by human MM cells. In present study, we investigated whether bisphosphonates and statins had any inhibitory effect on MIP-1 alpha secretion by human myeloma cells and the mechanism underlying this effect. In this study, we found that bisphosphonates and statins inhibited MIP-1 alpha mRNA and MIP-1 alpha 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-1 alpha (AML-1A) mRNA, a MIP-1 alpha 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-1 alpha secretion by MM cells. Therefore, use of MIP-1 alpha expression inhibitors such as bisphosphonates and statins may provide a new therapeutic approach to inhibiting tumour progression and bone destruction in MM patients.

• 出版日期2015