Regulation of survivin expression through Bcr-Abl/MAPK cascade: targeting survivin overcomes imatinib resistance and increases imatinib sensitivity in imatinib-responsive CML cells.
KBM5 cells, derived from a patient with blast crisis Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML), and imatinib-resistant KBM5 (KBM5-STI571) cells were found to express high levels of survivin. Inhibition of Bcr-Abl by imatinib significantly decreased survivin expression and cell viability in KBM5, but much less so in KBM5-STI571 cells. Inhibition of MEK, downstream of the Bcr-Abl signaling cascade decreased survivin expression and cell viability in both KBM5 and KBM5-STI571 cells. In addition, down-regulation of survivin by a survivin antisense oligonucleotide (Sur-AS-ODN) inhibited cell growth and induced maximal G2M block at 48 hours, whereas cell death was observed only at 72 hours in both KBM5 and KBM5-STI571 cells as shown by annexin V staining. Further, the combination of Sur-AS-ODN and imatinib induced more cell death in KBM5 cells than did either treatment alone. Down-regulating survivin also decreased colony-forming units (CFUs) in blast crisis CML patient samples. Our data therefore suggest that survivin is regulated by the Bcr-Abl/MAPK cascade in Ph+ CML. The facts that down-regulating survivin expression induced cell-growth arrest and subsequent cell death regardless of the cell response to imatinib and enhanced the sensitivity to imatinib suggest the potential therapeutic utility of this strategy in patients with CML, both imatinib sensitive and resistant.
Carter
Bing Z
BZ
Section of Molecular Hematology and Therapy, Department of Blood and Marrow Transplantation, University of Texas, M. D. Anderson Cancer Center, 1400 Holcombe Blvd, Unit 448, Houston, TX 77030, USA.
Mak
Duncan H
DH
Schober
Wendy D
WD
Cabreira-Hansen
Maria
M
Beran
Miloslav
M
McQueen
Teresa
T
Chen
Wenjing
W
Andreeff
Michael
M
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000068877:Imatinib Mesylate; D051034:Inhibitor of Apoptosis Proteins; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics*; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D000077022:Survivin
D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D001549:Benzamides; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D010879:Piperazines; D011743:Pyrimidines; D000077022:Survivin; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl