Bortezomib interferes with C-KIT processing and transforms the t(8;21)-generated fusion proteins into tumor-suppressing fragments in leukemia cells.
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.
Division of Molecular Carcinogenesis and Targeted Therapy for Cancer, State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology,  Chinese Academy of Sciences, Beijing 100101,  China.
Hai-Tong
HT
Fang
Bo
B
Zhang
Xiao-Fen
XF
Pan
Li
L
Gao
Tao
T
Zhen
Hong-Xia
HX
Zhao
Liang
L
Ma
Jun
J
Xie
Zi
Z
Liu
Xian-Jun
XJ
Yu
Xin
X
Cheng
Ting-Ting
TT
Feng
Feng-Xiang
FX
Zhang
Yong
Y
Yang
Zhong-Guo
ZG
Hu
Guo-Qing
GQ
Sheng
Yong-Long
YL
Chen
Sai-Juan
SJ
Chen
Zhu
Z
Chen
Guang-Biao
GB
Zhou
D017209:Apoptosis; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002891:Chromosomes, Human, Pair 21; D002898:Chromosomes, Human, Pair 8; D006801:Humans; D007938:Leukemia / Q000235:genetics / Q000473:pathology*; D010766:Phosphorylation; D011485:Protein Binding; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology*; D014178:Translocation, Genetic
D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib; D019009:Proto-Oncogene Proteins c-kit