論文 - 詳細
| RRC ID | 61871 |
|---|---|
| 著者 | Tsubaki M, Itoh T, Satou T, Imano M, Komai M, Ogawa N, Mukai J, Nishida S. |
| タイトル | Nitrogen-containing bisphosphonates induce apoptosis of hematopoietic tumor cells via inhibition of Ras signaling pathways and Bim-mediated activation of the intrinsic apoptotic pathway. |
| ジャーナル | Biochem Pharmacol |
| 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. |
| 巻・号 | 85(2) |
| ページ | 163-72 |
| 公開日 | 2013-1-15 |
| DOI | 10.1016/j.bcp.2012.10.009 |
| PII | S0006-2952(12)00681-8 |
| PMID | 23085435 |
| MeSH | 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 |
| IF | 4.96 |
| リソース情報 | |
| ヒト・動物細胞 | HL60(RCB0041) U-937 DE-4(RCB0435) |