CaMKII γ, a critical regulator of CML stem/progenitor cells, is a target of the natural product berbamine.
Bcr-Abl tyrosine kinase inhibitors (TKIs) have been a remarkable success for the treatment of Ph(+) chronic myeloid leukemia (CML). However, a significant proportion of patients treated with TKIs develop resistance because of leukemia stem cells (LSCs) and T315I mutant Bcr-Abl. Here we describe the unknown activity of the natural product berbamine that efficiently eradicates LSCs and T315I mutant Bcr-Abl clones. Unexpectedly, we identify CaMKII γ as a specific and critical target of berbamine for its antileukemia activity. Berbamine specifically binds to the ATP-binding pocket of CaMKII γ, inhibits its phosphorylation and triggers apoptosis of leukemia cells. More importantly, CaMKII γ is highly activated in LSCs but not in normal hematopoietic stem cells and coactivates LSC-related β-catenin and Stat3 signaling networks. The identification of CaMKII γ as a specific target of berbamine and as a critical molecular switch regulating multiple LSC-related signaling pathways can explain the unique antileukemia activity of berbamine. These findings also suggest that berbamine may be the first ATP-competitive inhibitor of CaMKII γ, and potentially, can serve as a new type of molecular targeted agent through inhibition of the CaMKII γ activity for treatment of leukemia.
Department of Hematology, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Hangzhou, China.
Ying
Y
Gu
Ting
T
Chen
Zhipeng
Z
Meng
Yichao
Y
Gan
Xiaohua
X
Xu
Guiyu
G
Lou
Hongzhi
H
Li
Xiaoxian
X
Gan
Hong
H
Zhou
Jinfen
J
Tang
Genbo
G
Xu
Liansheng
L
Huang
Xiaohong
X
Zhang
Yongming
Y
Fang
Kai
K
Wang
Shu
S
Zheng
Wendong
W
Huang
Rongzhen
R
Xu
D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D044182:Benzylisoquinolines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D015153:Blotting, Western; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008958:Models, Molecular; D009154:Mutation; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D001549:Benzamides; D044182:Benzylisoquinolines; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D000255:Adenosine Triphosphate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; C517603:CAMK1G protein, human; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1; C027870:berbamine