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Erythropoietin inhibits apoptosis in breast cancer cells via an Akt-dependent pathway without modulating in vivo chemosensitivity.

Publication ,  Journal Article
Hardee, ME; Rabbani, ZN; Arcasoy, MO; Kirkpatrick, JP; Vujaskovic, Z; Dewhirst, MW; Blackwell, KL
Published in: Mol Cancer Ther
February 2006

Evidence for erythropoietin signaling has been shown in several nonhematopoietic tissues, including many tumor types. Clinically, recombinant erythropoietin treatment of malignancy-related anemia has yet to be definitively associated with any modulation of chemotherapy or radiotherapy efficacy. Preclinically, recombinant erythropoietin has been shown to increase tumor oxygenation, but the direct effects of recombinant erythropoietin on tumor cells that express erythropoietin receptor are not yet fully characterized. This study examined the effects of exogenous recombinant erythropoietin on rodent mammary adenocarcinoma cells (R3230) in vitro and in vivo, and determined the effects of systemic recombinant erythropoietin on tumor growth delay in Taxol treatment. We showed that systemic recombinant erythropoietin treatment of rats bearing R3230 mammary carcinomas induced an increase in phospho-Akt levels within tumor cells. This was associated with a decrease in the frequency of apoptotic cells in tumors from recombinant erythropoietin-treated animals, but did not noticeably affect tumor growth rate. In vitro studies revealed that not only does recombinant erythropoietin induce Akt phosphorylation, but it also stimulates phosphorylation of p44/42 mitogen-activated protein kinases, Erk1 and Erk2. Activation of erythropoietin-mediated signaling in R3230 cells was associated with dose-dependent inhibition of apoptosis in response to Taxol treatment and serum starvation, an effect that was blocked by the addition of a phosphatidylinositol-3-kinase inhibitor. Despite its cytoprotective effects in vitro, recombinant erythropoietin did not significantly affect tumor growth delay in Taxol treatment. This study shows direct recombinant erythropoietin-mediated activation of specific intracellular signaling pathways in mammary adenocarcinoma cells in vivo and in vitro. Modulation of tumor apoptosis pathways by recombinant erythropoietin may have negative consequences by decreasing the chemosensitivity and radiosensitivity of erythropoietin receptor-positive breast tumors, although it did not have any obvious effects on growth with or without chemotherapy in this model.

Duke Scholars

Published In

Mol Cancer Ther

DOI

ISSN

1535-7163

Publication Date

February 2006

Volume

5

Issue

2

Start / End Page

356 / 361

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Recombinant Proteins
  • Receptors, Erythropoietin
  • Rats
  • Proto-Oncogene Proteins c-akt
  • Phosphorylation
  • Phosphatidylinositol 3-Kinases
  • Paclitaxel
  • Oncology & Carcinogenesis
  • Female
 

Citation

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ICMJE
MLA
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Hardee, M. E., Rabbani, Z. N., Arcasoy, M. O., Kirkpatrick, J. P., Vujaskovic, Z., Dewhirst, M. W., & Blackwell, K. L. (2006). Erythropoietin inhibits apoptosis in breast cancer cells via an Akt-dependent pathway without modulating in vivo chemosensitivity. Mol Cancer Ther, 5(2), 356–361. https://doi.org/10.1158/1535-7163.MCT-05-0196
Hardee, Matthew E., Zahid N. Rabbani, Murat O. Arcasoy, John P. Kirkpatrick, Zeljko Vujaskovic, Mark W. Dewhirst, and Kimberly L. Blackwell. “Erythropoietin inhibits apoptosis in breast cancer cells via an Akt-dependent pathway without modulating in vivo chemosensitivity.Mol Cancer Ther 5, no. 2 (February 2006): 356–61. https://doi.org/10.1158/1535-7163.MCT-05-0196.
Hardee ME, Rabbani ZN, Arcasoy MO, Kirkpatrick JP, Vujaskovic Z, Dewhirst MW, et al. Erythropoietin inhibits apoptosis in breast cancer cells via an Akt-dependent pathway without modulating in vivo chemosensitivity. Mol Cancer Ther. 2006 Feb;5(2):356–61.
Hardee, Matthew E., et al. “Erythropoietin inhibits apoptosis in breast cancer cells via an Akt-dependent pathway without modulating in vivo chemosensitivity.Mol Cancer Ther, vol. 5, no. 2, Feb. 2006, pp. 356–61. Pubmed, doi:10.1158/1535-7163.MCT-05-0196.
Hardee ME, Rabbani ZN, Arcasoy MO, Kirkpatrick JP, Vujaskovic Z, Dewhirst MW, Blackwell KL. Erythropoietin inhibits apoptosis in breast cancer cells via an Akt-dependent pathway without modulating in vivo chemosensitivity. Mol Cancer Ther. 2006 Feb;5(2):356–361.

Published In

Mol Cancer Ther

DOI

ISSN

1535-7163

Publication Date

February 2006

Volume

5

Issue

2

Start / End Page

356 / 361

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Recombinant Proteins
  • Receptors, Erythropoietin
  • Rats
  • Proto-Oncogene Proteins c-akt
  • Phosphorylation
  • Phosphatidylinositol 3-Kinases
  • Paclitaxel
  • Oncology & Carcinogenesis
  • Female