Erythropoietin reduces cisplatin-induced apoptosis in renal carcinoma cells via a PKC dependent pathway.
Anaemia which develops as a consequence of malignancies is often treated using recombinant human erythropoietin (rhEpo). Epo is now known as an anti-apoptotic factor for a wide range of cell types that express Epo receptors (EpoRs) and its co-use with cancer therapies can act detrimentally to diminish therapy-induced apoptosis. This had not been analyzed for renal cell carcinomas (RCCs). We examined the influence of rhEPO on the ability of cisplatin to induce apoptosis in RCCs. Two RCC cell lines (SN12K1 and ACHN) were compared with a non-RCC renal epithelial cell line (HK2). Cells were treated with 50 microM cisplatin with and without 200 IU/mL rhEpo and were compared for apoptosis, mitosis and protein expression of EpoR, nuclear factor-kappaB (NFkappaB), protein kinase C (PKC), Bcl-2, Bax and cyclin-D1. Experiments were repeated with PKC promotion (PMA, 20 nM) or inhibition (H7, 10 microM). rhEpo reduced cisplatin-induced apoptosis in RCCs (p < 0.01), compared with HK-2s. EpoR expression was increased only in SN12K1 with rhEpo, with and without cisplatin. NFkappaB, Bax and Bcl-2 expression was unchanged. PKC protein expression was significantly reduced in cisplatin-treated RCCs with rhEpo, correlating with reduced apoptosis. When the PKC pathway was inhibited in these cells, levels o apoptosis returned to normal for cisplatin treatment, indicating activation of the PKC pathway by rhEpo. PMA promotion increased mitosis only in the RCCs, with and without rhEpo (p < 0.05). In summary, rhEPO reduced cisplatin-induced apoptosis of RCCs and promoted their mitosis via PKC-dependent pathways. This information indicates caution for use of rhEpo in RCC patients for anemias.
Li
Jun
J
Centre for Kidney Disease Research UQ/PAH and Discipline of Molecular and Cellular Pathology, School of Medicine, University of Queensland, Herston, Brisbane, Australia.
Vesey
David A
DA
Johnson
David W
DW
Gobe
Glenda
G
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000494:pharmacology; D000740:Anemia / Q000188:drug therapy; D017209:Apoptosis / Q000187:drug effects*; D002292:Carcinoma, Renal Cell / Q000473:pathology*; D045744:Cell Line, Tumor / Q000166:cytology / Q000187:drug effects; D002945:Cisplatin / Q000037:antagonists & inhibitors*; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects; D004921:Erythropoietin / Q000009:adverse effects / Q000494:pharmacology*; D006801:Humans; D007680:Kidney Neoplasms / Q000473:pathology*; D008938:Mitosis / Q000187:drug effects; D009363:Neoplasm Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D011994:Recombinant Proteins; D015398:Signal Transduction / Q000187:drug effects*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D009363:Neoplasm Proteins; D011994:Recombinant Proteins; D004921:Erythropoietin; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate; D002945:Cisplatin