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Chemosensitization by erythropoietin through inhibition of the NF-κB rescue pathway

Oncogene volume 24, pages 737–745 (2005)Cite this article

Abstract

Two cell lines that exemplify erythropoietin (EPO) receptor-positive tumors, human renal carcinoma cell lines RCC and the myelomonocytic leukemia cell line U937, were investigated for the apoptosis-modulatory potential of EPO. Cells cultured in the presence of EPO exhibited an elevated apoptotic response to cancer chemotherapeutic agents such as daunorubicin (Dauno) and vinblastine (VBL). Chemosensitization by EPO did not involve an increase in p53 activation, yet correlated with enhanced Bax/Bak-dependent mitochondrial membrane perturbation and caspase maturation. In vitro monotherapy with Dauno or VBL induced the degradation of IκBα, provoked the translocation of NF-κB p65/50 to the nucleus and stimulated the expression of an NF-κB-activatable reporter gene. All these signs of NF-κB activation were perturbed in the presence of EPO. Inhibition of JAK2, one of the receptor-proximal elements of EPO-mediated signal transduction, greatly diminished the EPO-mediated chemosensitization and NF-κB inhibition. EPO lost its death-facilitating effects in the presence of an NF-κB inhibitor, underscoring the cause–effect relationship between EPO-mediated chemosensitization and NF-κB inhibition. Altogether, these results suggest that, at least in a specific subset of tumors, EPO receptor agonists can prevent activation of the NF-κB pathway, thereby enhancing the propensity of EPO receptor-positive tumor cells to undergo apoptosis.

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Abbreviations

anti-rhEPO:

anti-human EPO receptor antibody

Δψm:

mitochondrial transmembrane potential

DAPI, 4′:

6-diaminidino-2-phenylindole

Dauno:

daunorubicin

DiOC6(3), 3:

3′ dihexyloxacarbocyanine iodide

EPO:

erythropoietin

GAPDH:

glyceraldehyde-3-phosphate dehydrogenase

MMP:

mitochondrial membrane permeabilization

p53S15P:

p53 with phosphorylated serine 15

p53S46P:

p53 with phosphorylated serine 46

PI:

propidium iodide

VBL:

vinblastine

Boc-D.fmk:

BOAsp-fluoromethylketone

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Acknowledgements

This work has been supported by a special grant from Ligue Nationale contre le Cancer, as well as grants from the European Commission (QLK3-CT-2002-01956), Active p53 Ministère de la Recherche/Cancéropôle (to GK) and Association ‘Vaincre le Cancer’ (to GC).

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Author notes

  1. François Hirsch and Guido Kroemer: FH and GK share senior coauthorship.

Authors and Affiliations

  1. INSERM-U542, Paris XI University, Hôpital Paul Brousse, 16 avenue Paul Vaillant Couturier, F-94802, Villejuif, France

    Gabrielle Carvalho, Carmen Lefaucheur, Claire Cherbonnier, Marie-Françoise Bourgeade, Bernard Charpentier & François Hirsch

  2. CNRS-UMR8125, Institut Gustave Roussy, Pavillon de Recherche 1, 39 rue Camille-Desmoulins, F-94805, Villejuif, France

    Didier Métivier & Guido Kroemer

  3. IRSN, Fontenay-aux-Roses, France

    Alain Chapel

  4. INSERM U461, Faculte de Pharmacie Paris-Sud, rue JB Clement, Chatenay-Malabry, 92296, France

    Marc Pallardy

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  1. Gabrielle Carvalho
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Correspondence to François Hirsch or Guido Kroemer.

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Carvalho, G., Lefaucheur, C., Cherbonnier, C. et al. Chemosensitization by erythropoietin through inhibition of the NF-κB rescue pathway. Oncogene 24, 737–745 (2005). https://doi.org/10.1038/sj.onc.1208205

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