Abstract
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.
Copyright © 2012 Elsevier Inc. All rights reserved.
MeSH terms
-
Alendronate / adverse effects
-
Alendronate / pharmacology
-
Antineoplastic Agents / adverse effects
-
Antineoplastic Agents / pharmacology*
-
Apoptosis / drug effects*
-
Apoptosis Regulatory Proteins / antagonists & inhibitors*
-
Apoptosis Regulatory Proteins / genetics
-
Apoptosis Regulatory Proteins / metabolism
-
Bcl-2-Like Protein 11
-
Bone Density Conservation Agents / adverse effects
-
Bone Density Conservation Agents / pharmacology
-
Cell Line, Tumor
-
Cell Nucleus / drug effects
-
Cell Nucleus / metabolism
-
Cell Nucleus / pathology
-
Cell Survival / drug effects
-
Diphosphonates / adverse effects
-
Diphosphonates / pharmacology*
-
Gene Expression Regulation, Neoplastic / drug effects
-
Gene Silencing
-
Hematologic Neoplasms / drug therapy*
-
Hematologic Neoplasms / metabolism
-
Hematologic Neoplasms / pathology
-
Humans
-
Imidazoles / adverse effects
-
Imidazoles / pharmacology
-
MAP Kinase Signaling System / drug effects
-
Membrane Proteins / antagonists & inhibitors*
-
Membrane Proteins / genetics
-
Membrane Proteins / metabolism
-
Neoplasm Proteins / antagonists & inhibitors
-
Neoplasm Proteins / genetics
-
Neoplasm Proteins / metabolism
-
Protein Kinase Inhibitors / pharmacology
-
Protein Prenylation / drug effects
-
Proto-Oncogene Proteins / antagonists & inhibitors*
-
Proto-Oncogene Proteins / genetics
-
Proto-Oncogene Proteins / metabolism
-
Proto-Oncogene Proteins p21(ras) / antagonists & inhibitors*
-
Proto-Oncogene Proteins p21(ras) / metabolism
-
Signal Transduction / drug effects*
-
TOR Serine-Threonine Kinases / antagonists & inhibitors
-
TOR Serine-Threonine Kinases / metabolism
Substances
-
Antineoplastic Agents
-
Apoptosis Regulatory Proteins
-
BCL2L11 protein, human
-
Bcl-2-Like Protein 11
-
Bone Density Conservation Agents
-
Diphosphonates
-
Imidazoles
-
Membrane Proteins
-
Neoplasm Proteins
-
Protein Kinase Inhibitors
-
Proto-Oncogene Proteins
-
YM 529
-
cimadronate
-
MTOR protein, human
-
TOR Serine-Threonine Kinases
-
Proto-Oncogene Proteins p21(ras)
-
Alendronate