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Signalling pathways leading to neuroblastoma differentiation after serum withdrawal: HDL blocks neuroblastoma differentiation by inhibition of EGFR

Oncogene volume 24, pages 3309–3318 (2005)Cite this article

Abstract

Neuroblastoma is the second most common pediatric malignancy, characterized by a high rate of unexplained spontaneous remissions. Much progress has been made in understanding neuroblastoma differentiation triggered by certain agents such as retinoic acid. However, little is known about the signalling pathways that lead to differentiation of neuroblastoma cells due to serum withdrawal. We found that in Neuro2a neuroblastoma cells, EGFR, ERK1/2 and Akt showed increased phosphorylation after serum withdrawal, and that the activation of EGFR was necessary for the activation of Akt and ERK1/2. Inhibition of EGFR, ERK1/2 and PI3K blocked neuroblastoma differentiation after serum withdrawal. Interestingly, addition of high-density lipoprotein (HDL) abrogated serum-withdrawal induced neuroblastoma differentiation, as well as the activation of EGFR. Our results demonstrate a novel role for serum-derived lipoproteins in the control of receptor tyrosine kinase activity.

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Abbreviations

RTK:

receptor tyrosine kinase

EGFR:

EGF receptor

MAPK:

mitogen-activated protein kinase

PKB/Akt:

protein kinase B/Akt

PBS:

phosphate-buffered saline

CREB:

cAMP-responsive element binding protein

TBS:

Tris-buffered saline

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Acknowledgements

We would like to thank Dr JL Bos (University of Utrecht) for kindly providing the DN-PKB and DN-Ras contructs and Dr A Ullrich (MPI for Biochemistry, Munich) for the DN-EGFR construct, Dr K Baltensperger (University of Bern) for advice in microscopy, Dr HR Widmer (University of Bern, Switzerland) for the gift of tools and advice and MR Hess for artwork. This study was supported by the Papavramides Foundation, the Ehmann Foundation, and the Stiftung für Krebsbekämpfung

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Authors and Affiliations

  1. Division of Neuropathology, Institute of Pathology, University of Bern, Murtenstr. 31, CH-3010, Bern, Switzerland

    Maria Elephteria Evangelopoulos, Joachim Weis & Alex Krüttgen

  2. Institute of Neuropathology, University Hospital, RWTH Aachen, Pauwelsstr. 30, D-52074, Aachen, Germany

    Joachim Weis & Alex Krüttgen

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  1. Maria Elephteria Evangelopoulos
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Correspondence to Alex Krüttgen.

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Evangelopoulos, M., Weis, J. & Krüttgen, A. Signalling pathways leading to neuroblastoma differentiation after serum withdrawal: HDL blocks neuroblastoma differentiation by inhibition of EGFR. Oncogene 24, 3309–3318 (2005). https://doi.org/10.1038/sj.onc.1208494

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