Spred2 is involved in imatinib-induced cytotoxicity in chronic myeloid leukemia cells.
Spreds, a recently established class of negative regulators of the Ras-ERK (extracellular signal-regulated kinase) pathway, are involved in hematogenesises, allergic disorders and tumourigenesis. However, their role in hematologic neoplasms is largely unknown. Possible effects of Spreds on other signal pathways closely related to Ras-ERK have been poorly investigated. In this study, we investigated the in vitro effects of Spred2 on chronic myeloid leukemia (CML) cells. In addition to inhibiting the well-established Ras-ERK cascade, adenovirus-mediated Spred2 over-expression inhibits constitutive and stem cell factor (SCF)-stimulated sphingosine kinase-1 (SPHK1) and Mcl-1 expression, as well as inhibiting proliferation and inducing apoptosis in CML cells. In K562 cells and primary CML cells, imatinib induces endogenous Spred2 expression. Spred2 silencing by stable RNA interference partly protects K562 cells against imatinib-induced apoptosis. Together, these data implicate Spred2 in imatinib-induced cytotoxicity in CML cells, possibly by inhibiting the Ras-ERK cascade and the pro-survival signaling molecules SPHK1 and Mcl-1. These findings reveal potential targets for selective therapy of CML.
Liu
Xiao-Yun
XY
Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing 100850, PR China.
Yang
Yue-Feng
YF
Wu
Chu-Tse
CT
Xiao
Feng-Jun
FJ
Zhang
Qun-Wei
QW
Ma
Xiao-Ni
XN
Li
Qing-Fang
QF
Yan
Jun
J
Wang
Hua
H
Wang
Li-Sheng
LS
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001549:Benzamides; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020868:Gene Silencing; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D000099157:Sphingosine Kinase
D000970:Antineoplastic Agents; D001549:Benzamides; D020169:Caspases; D048049:Extracellular Signal-Regulated MAP Kinases; D000068877:Imatinib Mesylate; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D017853:Phosphotransferases (Alcohol Group Acceptor); D010879:Piperazines; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011743:Pyrimidines; D012097:Repressor Proteins; D000099157:Sphingosine Kinase; C500760:SPRED2 protein, human