Impaired downregulation following erythropoietin receptor activation in non-small cell lung carcinoma.
Recent evidence confirms the presence of erythropoietin receptors on a variety of cancer cells. This has raised concerns about the use of erythropoiesis-stimulating agents in the treatment of cancer-related anemia. Having previously identified expression of functional erythropoietin receptors in a non-small cell lung carcinoma cell line, H838, which activated key signaling pathways in response to erythropoietin stimulation, we now demonstrate impaired downregulation of the erythropoietin receptor in these tumor cells. The erythropoietin receptor is not ubiquitinated following erythropoietin stimulation in this cancer cell line, and there is no turnover of the receptor in either unstimulated or stimulated cells. Compounding this blunted response is impaired SOCS3 induction downstream of erythropoietin stimulation and an extremely delayed SOCS1 response. If this finding in non-small cell lung carcinoma is a widespread phenomenon, then impaired erythropoietin receptor downregulation and degradation in tumor cells has clinical implications for those patients receiving erythropoiesis-stimulating agents for cancer-related anemia.
Dunlop
Elaine A
EA
Haematology Research Group, Centre for Cancer Research and Cell Biology, Queen's University, Belfast, United Kingdom. e.dunlop@qub.ac.uk
Maxwell
Alexander P
AP
Lappin
Terence R J
TR
D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D003513:Cycloheximide / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D004921:Erythropoietin / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism*; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017467:Receptors, Erythropoietin / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism; D014452:Ubiquitins / Q000378:metabolism
D012333:RNA, Messenger; D017467:Receptors, Erythropoietin; D011994:Recombinant Proteins; D050826:Suppressor of Cytokine Signaling Proteins; D014452:Ubiquitins; D004921:Erythropoietin; D003513:Cycloheximide; D046988:Proteasome Endopeptidase Complex