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Downmodulation of ERK protein kinase activity inhibits VEGF secretion by human myeloma cells and myeloma-induced angiogenesis

Leukemia volume 18, pages 628–635 (2004)Cite this article

Abstract

The mitogen-activated protein (MAP) cascade leading to the activation of extracellular signal-regulated kinases 1/2 (ERK1/2) is critical for regulating myeloma cell growth; however, the relationship of ERK1/2 activity with vascular endothelial growth factor (VEGF) production and the effects of its downmodulation in myeloma cells are not elucidated. We found that the treatment with MAP/ERK kinase 1 (MEK1) inhibitors PD98059 or PD184352 produced a reduction of phosphorylated ERK1/2 (p-ERK1/2) levels in myeloma cells of more than 80% and prevented the increase of p-ERK1/2 induced by interleukin-6 (IL-6). MEK1 inhibitors also induced a significant inhibition of myeloma cell proliferation and blunted the stimulatory effect induced by IL-6. A significant inhibition of basal VEGF secretion by myeloma cells as well as a suppression of the stimulatory effect of IL-6 on VEGF was observed by either PD98059 or PD184352. Moreover, we also found that the PI3K kinase inhibitors, but not p38 MAPK inhibitors, reduced VEGF secretion by myeloma cells and increase the inhibitory effect of MEK1 inhibitors. In an ‘in vitro’ model of angiogenesis, we found that MEK1 inhibitors impair vessel formation induced by myeloma cells and restored by VEGF treatment, suggesting that the downmodulation of ERK1/2 activity reduces myeloma-induced angiogenesis by inhibiting VEGF secretion.

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Acknowledgements

This study was supported by grants from the ‘Associazione Italiana per la Ricerca sul Cancro’ (AIRC), from the ‘Ministero dell’Istruzione dell'Università e della Ricerca Scientifica' (MIUR FIN, FIL and ‘Progetto Strategico Oncologia SP/4: Terapia preclinica molecolare in oncologia’); NG and PL are recipient of a grant from ‘Associazione Chiara Tassoni per la Lotta contro la Leucemia e il Cancro-Parma’. We wish to thank Dr Judith S Sebolt Leopold (Cancer Molecular Sciences, Pfizer Global Research and Development, Ann Arbor, MI, USA) who kindly provided us the compound PD184352.

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  1. N Giuliani and P Lunghi: Both these authors contributed equally to this work

Authors and Affiliations

  1. Chair of Hematology, BMT Unit, University of Parma, Parma, Italy

    N Giuliani, F Morandi, S Colla, S Bonomini, M Hojden & V Rizzoli

  2. Department of Clinical Sciences, University of Parma, Parma, Italy

    P Lunghi & A Bonati

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  1. N Giuliani
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Correspondence to N Giuliani.

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Giuliani, N., Lunghi, P., Morandi, F. et al. Downmodulation of ERK protein kinase activity inhibits VEGF secretion by human myeloma cells and myeloma-induced angiogenesis. Leukemia 18, 628–635 (2004). https://doi.org/10.1038/sj.leu.2403269

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