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Phosphorylation status of c-Kit and Epo receptors, and the presence of wild-type p53 confer in vitro resistance of murine erythroleukemic cells to Celecoxib

Oncogene volume 23, pages 2305–2314 (2004)Cite this article

Abstract

It is well established that selective COX-2 inhibitors exhibit potent effects against progression of select solid tumours. However, their effects on liquid tumours have not been fully established. By taking advantage of murine Friend Disease we have shown a strong antileukemic effect of celecoxib by determining novel in vitro targets. Western blot analyses revealed the expression of COX-2 in a panel of Friend Virus-transformed, splenic-derived primary erythroleukemic blasts and established cell lines generated in our laboratory. We have shown that celecoxib at concentrations as low as 20 μ M significantly suppresses proliferation of the selected murine erythroleukemia cell line HB60-5. The greatest proliferative inhibition was seen at 40 μ M of celecoxib, resulting in apoptosis. Our results also demonstrate that treatment of the established murine erythroleukemia cell line HB60-5 with celecoxib results in suppression of c-Kit and erythropoietin receptor (Epo-R) phosphorylation resulting in apoptosis, likely through decreased levels of survival factors. However, upon overexpression of c-Kit alone in these cells a significant increase in survival and twofold increase in proliferation in the presence of celecoxib were observed (P<0.05). Finally, since responsiveness of our murine erythroleukemia cell lines to celecoxib is above the reported physiologically achievable levels in vivo, we have provided in vitro evidence to suggest that reduced sensitivity of erythroleukemic cells to lower doses of celecoxib may be a consequence of the loss of wild-type p53. These findings are pivotal in addressing potential discrepancies associated with sensitivity of murine erythroleukemic cells to celecoxib in vitro versus in vivo.

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Acknowledgements

We are grateful for Dr R. Rottapel for his kind gift of the GP+E-86/c-Kit+, /LXS packaging cell lines. We also thank Drs J. Filmus, S. Benchimol and B. Pak for their comments concerning the work presented in this study, and also Ms. Lynda Woodcock for assistance in the preparation of the manuscript. This work was supported by a grant from the National Cancer Institute of Canada (NCIC) and a contract fund from Pharmacia/Monsanto. Dave Cervi and Amandine HL Truong are supported by studentships from the Canadian Institute for Health Research.

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Authors and Affiliations

  1. Department of Medical Biophysics, Sunnybrook and Women's College Health Sciences Centre and Toronto Sunnybrook Regional Cancer Centre, University of Toronto, M4N 3M5, Ontario, Canada

    David Cervi, Amandine H L Truong, Jane S Lee, Natasha Sukhai, You-Jun Li & Yaacov Ben-David

  2. IPSOGEN, 2 Bd Luce 13008, Marseille, France

    Alane Koki

  3. Department of Molecular and Cellular Biology, Sunnybrook and Women's College Health Sciences Centre and Toronto Sunnybrook Regional Cancer Centre, University of Toronto, M4N 3M5, Ontario, Canada

    Yaacov Ben-David

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  1. David Cervi
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Correspondence to Yaacov Ben-David.

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Cervi, D., Truong, A., Lee, J. et al. Phosphorylation status of c-Kit and Epo receptors, and the presence of wild-type p53 confer in vitro resistance of murine erythroleukemic cells to Celecoxib. Oncogene 23, 2305–2314 (2004). https://doi.org/10.1038/sj.onc.1207400

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