Inhibition of IGF-IR tyrosine kinase induces apoptosis and cell cycle arrest in imatinib-resistant chronic myeloid leukaemia cells

Ping Shi, Joya Chandra, Xiaoping Sun, Mate Gergely, Jorge E. Cortes, Guillermo Garcia-Manero, Ralph B. Arlinghaus, Raymond Lai, Hesham M. Amin

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1777-1792
Number of pages16
JournalJournal of Cellular and Molecular Medicine
Volume14
Issue number6 B
DOIs
StatePublished - Jun 1 2010
Externally publishedYes

Keywords

  • BCR-ABL
  • Chronic myeloid leukaemia
  • IGF-IR
  • Imatinib mesylate
  • Picropodophyllin

ASJC Scopus subject areas

  • Molecular Medicine
  • Cell Biology

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