Cisplatin up-regulates the in vivo biosynthesis and degradation of renal polyamines and c-Myc expression.
Time-dependent changes in polyamine metabolism and c-Myc expression are reported in kidney of mice treated with cisplatin, a widely used anticancer drug. We show that cisplatin significantly induces the expression of two enzymes critical to proper homeostasis of cellular polyamines, ornithine decarboxylase (ODC) and spermidine/spermine N1-acetyltransferase (SSAT). We also document the cross-talk between signalling pathway(s) induced by cisplatin injury to renal tubules and the testosterone/androgen receptor pathway. Their interaction results in a decrease in testosterone-induced ODC activity and ODC mRNA level, and in differential modulation of SSAT expression. Moreover, cisplatin and antifolate CB 3717, another nephrotoxic drug examined, severalfold up-regulate expression of c-Myc mRNA, albeit with different kinetics. However, cisplatin, contrary to CB 3717, does not induce renal hepatocyte growth factor (HGF)/c-Met expression being without effect on HGF mRNA level and significantly down-regulating c-Met transmembrane receptor message. In conclusion, these in vivo studies document significant cisplatin-induced modulation of polyamine biosynthesis/degradation and up-regulation of c-Myc expression, and suggest that c-Myc transcription factor is involved in the induction of ODC in kidney injured with antifolate, but not with cisplatin.
Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteur Street, 02-093 Warsaw.
Agnieszka
A
Stachurska
Magdalena
M
Dudkowska
Alicja
A
Czopek
Małgorzata
M
Manteuffel-Cymborowska
Barbara
B
Grzelakowska-Sztabert
D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015317:Biogenic Polyamines / Q000096:biosynthesis* / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology*; D005260:Female; D017228:Hepatocyte Growth Factor / Q000235:genetics; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D009955:Ornithine Decarboxylase / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*; D000099228:Diamine N-Acetyltransferase
D000123:Acetyltransferases; D015317:Biogenic Polyamines; D002945:Cisplatin; D017228:Hepatocyte Growth Factor; D009955:Ornithine Decarboxylase; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D000099228:Diamine N-Acetyltransferase