Inhibition of IGF-IR tyrosine kinase induces apoptosis and cell cycle arrest in imatinib-resistant chronic myeloid leukaemia cells.
Although signalling through the type I insulin-like growth factor receptor (IGF-IR) maintains the survival of haematopoietic cells, a specific role of IGF-IR in haematological neoplasms remains largely unknown. Chronic myeloid leukaemia (CML) is the most common subtype of chronic myeloproliferative diseases. Typically, CML evolves as a chronic phase (CP) disease that progresses into accelerated (AP) and blast phase (BP) stages. In this study, we show that IGF-IR is universally expressed in four CML cell lines. IGF-IR was expressed in only 30% and 25% of CP and AP patients, respectively, but its frequency of expression increased to 73% of BP patients. Increased expression levels of IGF-IR with CML progression was supported by quantitative real-time PCR that demonstrated significantly higher levels of IGF-IR mRNA in BP patients. Inhibition of IGF-IR decreased the viability and proliferation of CML cell lines and abrogated their growth in soft agar. Importantly, inhibition of IGF-IR decreased the viability of cells resistant to imatinib mesylate including BaF3 cells transfected with p210 BCR-ABL mutants, CML cell lines and primary neoplastic cells from patients. The negative effects of inhibition of IGF-IR were attributable to apoptosis and cell cycle arrest due to alterations of downstream target proteins. Our findings suggest that IGF-IR could represent a potential molecular target particularly for advanced stage or imatinib-resistant cases.
Shi
Ping
P
Department of Hematopathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
Chandra
Joya
J
Sun
Xiaoping
X
Gergely
Mate
M
Cortes
Jorge E
JE
Garcia-Manero
Guillermo
G
Arlinghaus
Ralph B
RB
Lai
Raymond
R
Amin
Hesham M
HM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D051379:Mice; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D017526:Receptor, IGF Type 1; D016044:Fusion Proteins, bcr-abl