4.7 Article

Exposure of neuroblastoma cell lines to imatinib results in the upregulation of the CDK inhibitor p27KIP1 as a consequence of c-Abl inhibition

Journal

BIOCHEMICAL PHARMACOLOGY
Volume 92, Issue 2, Pages 235-250

Publisher

PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2014.09.016

Keywords

Imatinib; Neuroblastoma; p27(KIP1); c-Abl; CDK2; pRb

Funding

  1. Progetti di ricerca finanziati dall'Universita' degli Studi di Torino
  2. Regione Piemonte, Ricerca Scientifica Applicata project [A189]
  3. TAKTIC consortium [FP7-SME-2012-315746-TAKTIC]

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Imatinib mesylate is a tyrosine kinase inhibitor with selectivity for abelson tyrosine-protein kinase 1 (c-Abl), breakpoint cluster region (Bcr)-Abl fusion protein (Bcr-Abl), mast/stem cell growth factor receptor Kit (c-Kit), and platelet-derived growth factor receptor (PDGFR). Previous studies demonstrated that imatinib in the low micromolar range exerted antiproliferative effects on neuroblastoma cell lines. However, although neuroblastoma cells express c-Kit and PDGFR, the imatinib concentrations required to achieve significant growth inhibitory effects (>= 10 mu M) are substantially higher than those required for inhibition of ligand-induced phosphorylation of wild type c-Kit and PDGFR (<= 1 mu M), suggesting that additional mechanisms are responsible for the antitumor activity of imatinib on these cells. In this study, we show that treatment of neuroblastoma cell lines with 1-15 mu M imatinib resulted in a dose dependent inhibition of 5-bromo-2'-deoxyuridine (BrdU) incorporation into newly synthesized DNA. The antiproliferative effect of imatinib was dependent on the upregulation of the cyclin-dependent kinase (CDK) inhibitor p27(KIP1) in the nuclear compartment as a result of increased p27(KIP1) protein stability. We demonstrate that the mechanism of p27(KIP1) stabilization relied on inhibition of p27(KIP1) phosphorylation on tyrosine residues by c-Abl. We provide evidence that in neuroblastoma cell lines a significant fraction of cellular c-Abl is phosphorylated on Tyr-245, consistent with an open and active conformation. Notably, exposure to imatinib did not affect Tyr-245 phosphorylation. Given the low affinity of active c-Abl for imatinib, these data provide a molecular explanation for the relatively high imatinib concentrations required to inhibit neuroblastoma cell proliferation. (C) 2014 Elsevier Inc. All rights reserved.

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