Sphingosine kinase-1 mediates BCR/ABL-induced upregulation of Mcl-1 in chronic myeloid leukemia cells.
The signaling mechanisms responsible for BCR/ABL-induced regulation of Mcl-1 expression in chronic myelogenous leukemia (CML) cells remain unclear. In this study, we show that BCR/ABL could upregulate sphingosine kinase-1 (SPK1) expression via multiple signal pathways, including mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K) and Janus kinase 2 (JAK2), leading to increase cellular SPK1 activity in CML cells. Retrovirus-mediated overexpression of bcr-abl gene in NIH-3T3, Ba/F3 and HL-60 cells results in upregulation and increased cellular activity of SPK1, whereas treatment of CML cells with specific inhibitors of the BCR/ABL, PI3K, MAPK and JAK2 pathways decreases BCR/ABL-induced SPK1 expression and cellular activity. BCR/ABL also induces upregulation of Mcl-1 expression in CML cells. Inhibition of SPK1 by adenovirus-mediated transfer of small interfering RNA or N,N-dimethylsphingosine reduced expression of Mcl-1 in CML cells. Our data indicated that BCR/ABL induces SPK1 expression and increases its cellular activity, leading to upregulation of Mcl-1 in CML cells. SPK1 silencing enhances the STI571-induced apoptosis of CML cell lines. It is suggested that SPK1 may be a potential therapeutic target in CML.
Li
Q-F
QF
Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing, PR China.
Huang
W-R
WR
Duan
H-F
HF
Wang
H
H
Wu
C-T
CT
Wang
L-S
LS
D000818:Animals; D001549:Benzamides; D016044:Fusion Proteins, bcr-abl / Q000502:physiology*; D006801:Humans; D000068877:Imatinib Mesylate; D053614:Janus Kinase 2 / Q000502:physiology; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics*; D051379:Mice; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D041681:NIH 3T3 Cells; D009363:Neoplasm Proteins / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000502:physiology*; D010879:Piperazines / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D011743:Pyrimidines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction; D015854:Up-Regulation; D000099157:Sphingosine Kinase
D001549:Benzamides; D016044:Fusion Proteins, bcr-abl; D000068877:Imatinib Mesylate; D053614:Janus Kinase 2; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D011743:Pyrimidines; D034741:RNA, Small Interfering; D000099157:Sphingosine Kinase; C579094:Mcl1 protein, mouse; C507924:JAK2 protein, human