Nitrogen-containing bisphosphonates induce apoptosis of hematopoietic tumor cells via inhibition of Ras signaling pathways and Bim-mediated activation of the intrinsic apoptotic pathway

作者：Tsubaki Masanobu; Itoh Tatsuki; Satou Takao; Imano Motohiro; Komai Makiko; Ogawa Naoki; Mukai Junji; Nishida Shozo^*

来源：Biochemical Pharmacology, 2013, 85(2): 163-172.

DOI：10.1016/j.bcp.2012.10.009

• Nitrogen-containing bisphosphonates
• Bim
• Ras
• ERK1/2
• mTOR

Nitrogen-containing bisphosphonates (N-Bps) induce apoptosis in tumor cells by inhibiting the prenylation of small G-proteins. However, the details of the apoptosis-inducing mechanism remain obscure. The present study showed that the induction of apoptosis by N-Bps in hematopoietic tumor cells is mediated by mitochondrial apoptotic signaling pathways, which are activated by the suppression of geranylgeranyl pyrophosphate (GGPP) biosynthesis. Furthermore, N-BPs decreased the levels of phosphorylated extracellular signal-regulated kinase (ERK) and mTOR via suppression of Ras prenylation and enhanced Bim expression. The present results indicated that N-BPs induce apoptosis by decreasing the mitochondrial transmembrane potential, increasing the activation of caspase-9 and caspase-3, and enhancing Bim expression through inhibition of the Ras/MEK/ERK and Ras/mTOR pathways. The accumulation of N-BPs in bones suggests that they may act more effectively on tumors that have spread to bones or on Ras-variable tumors. This is the first study to show that the specific molecular pathways of N-BP-induced apoptosis.

• 出版日期2013-1-15