Induction of signalling in non-erythroid cells by pharmacological levels of erythropoietin.
Erythropoiesis is maintained by the hormone erythropoietin (Epo) binding to its cognate receptor (EpoR) on erythroid progenitor cells. The Epo-EpoR interaction initiates a signal transduction process that regulates the survival, growth and differentiation of these cells. Originally perceived as highly lineage-restricted, Epo is now recognised to have pleiotropic effects extending beyond the maintenance of red cell mass. Functional interactions between Epo and EpoR have been demonstrated in numerous cells and tissues. EpoR expression on neoplastic cells leads to concern that recombinant human erythropoietin, used to treat anaemia in cancer patients, may augment tumour growth. Here we demonstrate that EPO, at pharmacological concentrations, can activate three major signalling cascades, viz. the Jak2/STAT5, Ras/ERK and PI3K/Akt pathways in non-small cell lung carcinoma (NSCLC) cell lines. EpoR synthesis is normally under the control of GATA-1, but NSCLC cells exhibit decreased GATA-1 levels compared to GATA-2, -3 and -6, suggesting that GATA-1 is not essential for EpoR production. The increased Epo-induced signalling was not associated with a growth advantage for the NSCLC cells.
Dunlop
E A
EA
Centre for Cancer Research and Cell Biology, Queens University Belfast, and Haematology Department, Belfast City Hospital, UK.
Percy
M J
MJ
Boland
M P
MP
Maxwell
A P
AP
Lappin
T R
TR
D002289:Carcinoma, Non-Small-Cell Lung; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D041905:Erythroid Cells / Q000166:cytology / Q000378:metabolism*; D004921:Erythropoietin / Q000378:metabolism* / Q000494:pharmacology*; D050982:GATA1 Transcription Factor / Q000235:genetics; D050989:GATA2 Transcription Factor / Q000235:genetics; D050990:GATA3 Transcription Factor / Q000235:genetics; D050991:GATA4 Transcription Factor / Q000235:genetics; D050992:GATA5 Transcription Factor / Q000235:genetics; D050993:GATA6 Transcription Factor / Q000235:genetics; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D008175:Lung Neoplasms; D012333:RNA, Messenger / Q000032:analysis; D017467:Receptors, Erythropoietin / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology*
D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; D050989:GATA2 Transcription Factor; C494711:GATA2 protein, human; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; D050991:GATA4 Transcription Factor; C484170:GATA4 protein, human; D050992:GATA5 Transcription Factor; C494755:GATA5 protein, human; D050993:GATA6 Transcription Factor; C494759:GATA6 protein, human; D012333:RNA, Messenger; D017467:Receptors, Erythropoietin; D011994:Recombinant Proteins; D004921:Erythropoietin