论文题目: | Bortezomib interferes with C-KIT processing and transforms the t(8;21)-generated fusion proteins into tumor-suppressing fragments in leukemia cells |
论文题目英文: | |
作者: | 方海同①,张波①,#Xiaofen Pan,#Li Gao,#Tao Zhen,#Hongxia Zhao,马亮,#Jun Xie,刘姿,余贤军,Xin Cheng,#Tingting Feng,#Fengxiang Zhang,#Yong Yang,#Zhongguo Hu,#Guoqing Sheng,#Yonglong Cheng,#陈赛娟*,#陈竺*,周光飚* |
论文出处: | |
年: | 2012 |
卷: | 109 |
期: | 7 |
页: | 2521-2526 |
联系作者: | 周光飚 |
发表期刊: | PNAS |
ISSN: | |
第一作者所在部门: | |
收录类别: | |
论文连接 | http://www.pnas.org/content/early/2012/01/26/1121341109.short |
影响因子: | |
摘要: | The boronic acid dipeptide bortezomib inhibits the chymotrypsin-like activity of the 26S proteasome and shows significant therapeutic efficacy in multiple myeloma. However, recent studies suggest that bortezomib may have more complex mechanisms of action in treating cancer. We report here that the endocytosis and lysosomal degradation of the receptor tyrosine kinase C-KIT are required for bortezomib- but not tyrosine kinase inhibitor imatinib-caused apoptosis of t(8;21) leukemia and gastrointestinal stromal tumor cells, suggesting that C-KIT may recruit an apoptosis initiator. We show that C-KIT binds and phosphorylates heat shock protein 90β (Hsp90β), which sequestrates apoptotic protease activating factor 1 (Apaf-1). Bortezomib dephosphorylates pHsp90β and releases Apaf-1. Although the activated caspase-3 is not sufficient to cause marked apoptosis, it cleaves the t(8;21) generated acute myeloid leukemia 1-eight twenty one (AML1-ETO) and AML1-ETO9a fusion proteins, with production of cleavage fragments that perturb the functions of the parental oncoproteins and further contribute to apoptosis. Notably, bortezomib exerts potent therapeutic efficacy in mice bearing AML1-ETO9a–driven leukemia. These data show that C-KIT-pHsp90β-Apaf-1 cascade is critical for some malignant cells to evade apoptosis, and the clinical therapeutic potentials of bortezomib in C-KIT–driven neoplasms should be further explored. |
英文摘要: | |
外单位作者单位: |