TY - JOUR
T1 - Inhibition of IGF-IR tyrosine kinase induces apoptosis and cell cycle arrest in imatinib-resistant chronic myeloid leukaemia cells
AU - Shi, Ping
AU - Chandra, Joya
AU - Sun, Xiaoping
AU - Gergely, Mate
AU - Cortes, Jorge E.
AU - Garcia-Manero, Guillermo
AU - Arlinghaus, Ralph B.
AU - Lai, Raymond
AU - Amin, Hesham M.
PY - 2010/6
Y1 - 2010/6
N2 - 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.
AB - 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.
KW - BCR-ABL
KW - Chronic myeloid leukaemia
KW - IGF-IR
KW - Imatinib mesylate
KW - Picropodophyllin
UR - http://www.scopus.com/inward/record.url?scp=77955138504&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77955138504&partnerID=8YFLogxK
U2 - 10.1111/j.1582-4934.2009.00795.x
DO - 10.1111/j.1582-4934.2009.00795.x
M3 - Article
C2 - 19508387
AN - SCOPUS:77955138504
SN - 1582-1838
VL - 14
SP - 1777
EP - 1792
JO - Journal of Cellular and Molecular Medicine
JF - Journal of Cellular and Molecular Medicine
IS - 6 B
ER -