Open AccessInhibition of IGF‐IR tyrosine kinase induces apoptosis and cell cycle arrest in imatinib‐resistant chronic myeloid leukaemia cells
Author(s) -
Shi Ping,
Chandra Joya,
Sun Xiaoping,
Gergely Mate,
Cortes Jorge E.,
GarciaManero Guillermo,
Arlinghaus Ralph B.,
Lai Raymond,
Amin Hesham M.
Publication year - 2010
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/j.1582-4934.2009.00795.x
Subject(s) - imatinib , cancer research , imatinib mesylate , tyrosine kinase , cell cycle , biology , haematopoiesis , apoptosis , viability assay , cell culture , growth factor , cell growth , myeloid leukemia , immunology , medicine , receptor , signal transduction , stem cell , microbiology and biotechnology , biochemistry , genetics
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.