Inhibition of MEK/ERK signaling induces apoptosis of acute myelogenous leukemia cells via inhibition of eukaryotic initiation factor 4E-binding protein 1 and down-regulation of Mcl-1 |
| |
Authors: | Chie Nishioka Takayuki Ikezoe Jing Yang Akihito Yokoyama |
| |
Institution: | (1) Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Oko-cho, Nankoku Kochi, 783-8505, Japan;(2) Japanese Society for the Promotion of Science (JSPS), Chiyodaku, Tokyo, Japan; |
| |
Abstract: | We previously showed that the MEK inhibitor AZD6244 induced apoptosis in acute myelogenous leukemia (AML) HL60 cells. However,
the mechanisms of AZD6244 to induce apoptosis remain to be fully elucidated. This study found that exposure of HL60 cells
to AZD6244 down-regulated the levels of phosphor (p)-4E-binding protein 1 (4E-BP1), a substrate of mammalian target of rapamycin
complex 1 (mTORC1), and anti-apoptotic protein Mcl-1. On the other hand, exposure of EOL-1 and MOLM13 cells to AZD6244 failed
to induce apoptosis and levels of p-4E-BP1 and Mcl-1 were not down-regulated in these cells. These observations prompted us
to hypothesize that down-regulation od 4E-BP1 and Mcl-1 might play an important role in AZD6244-mediated apoptosis. As expected,
down-regulation of 4E-BP1 by an siRNA sensitized EOL-1 cells to AZD6244-mediated apoptosis in parallel with down-regulation
of Mcl-1. Moreover, we found that blockade of mTORC1 by RAD001 synergistically enhanced the action of AZD6244 in leukemia
cells. |
| |
Keywords: | |
本文献已被 SpringerLink 等数据库收录! |
|