Erythropoietin treatment of human ovarian cancer cells results in enhanced signaling and a paclitaxel-resistant phenotype.
Erythropoietin (Epo), a glycoprotein hormone that is the principal regulator of erythropoiesis, is known to act also on nonhematopoietic cell types. Epo receptors have been reported on several normal and neoplastic human cells and tissues, including ovarian cancer cells. We found that long-term Epo treatment of A2780 cells resulted in the development of a phenotype exhibiting both enhanced Epo signaling, evidenced by increased peak levels of phospho-Erk1/2 and increased paclitaxel resistance. This phenotypic effect was specific for paclitaxel, since no change in cisplatin or carboplatin sensitivity was observed. In addition, the change in phenotype was stable, even after the removal of Epo. Measurement of mono- and oligonucleosome formation revealed that long-term Epo treated A2780 cells exhibited markedly less apoptosis than nonerythropoietin treated cells at essentially all concentrations of paclitaxel tested. Western blot analyses revealed that the long-term Epo treated cells had significantly reduced expression of apoptosis-related proteins Bcl-2 and Bcl-10. These findings may have implications for the clinical use of recombinant human Epo and other erythropoiesis stimulating agents to correct anemia in paclitaxel-treated cancer patients.
Solar
Peter
P
Laboratory for Cell and Molecular Biology, Division of Hematology and Oncology, Beth Israel Deaconess Medical Center,Department of Medicine, Harvard Medical School, Boston, MA, USA.
Feldman
Laurie
L
Jeong
Jee-Yeong
JY
Busingye
Jacqueline R
JR
Sytkowski
Arthur J
AJ
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D000074018:B-Cell CLL-Lymphoma 10 Protein; D016190:Carboplatin / Q000494:pharmacology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004921:Erythropoietin / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D010051:Ovarian Neoplasms / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry; D015398:Signal Transduction
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D000074018:B-Cell CLL-Lymphoma 10 Protein; C118591:BCL10 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D004921:Erythropoietin; D016190:Carboplatin; D017239:Paclitaxel; D002945:Cisplatin