Cisplatin-induced apoptosis of immortalized mouse proximal tubule cells is mediated by interleukin-1 beta converting enzyme (ICE) family of proteases but inhibited by overexpression of Bcl-2.
Cisplatin is known to induce serious renal damage including acute renal failure, the major site of renal injury appears to be localized to the third segment of the proximal tubule (S3). Apoptosis occurs during a variety of acute injuries to tubule cell. The purpose of this study was to determine whether cisplatin induces apoptosis of immortalized mouse S3 cells, and to define the intracellular pathways leading to cell death. S3 cells exposed to cisplatin exhibited biochemical, morphological, and flow cytometric changes characteristic of apoptosis associated with slight necrosis. Cisplatin-induced apoptosis could be inhibited by overexpression of crmA, a cowpox virus gene, of which the product is known to suppress activities of the interleukin-1 beta converting enzyme (ICE) family proteases. On the other hand, overexpression of bcl-2, an antiapoptotic oncogene, rendered S3 cells partially resistant to cisplatin. These results indicate that cisplatin-induced proximal tubule damage is associated with apoptosis, which is positively modulated by the ICE family of proteases and negatively by the product of bcl-2.
Takeda
M
M
Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Tokyo, Japan.
Kobayashi
M
M
Shirato
I
I
Osaki
T
T
Endou
H
H
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D020170:Caspase 1; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000633:toxicity*; D003546:Cysteine Endopeptidases / Q000494:pharmacology*; D053938:DNA Fragmentation / Q000187:drug effects / Q000235:genetics; D005434:Flow Cytometry; D019204:GTP-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D051379:Mice; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000235:genetics
D000970:Antineoplastic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D011505:Protein-Tyrosine Kinases; D003546:Cysteine Endopeptidases; D020170:Caspase 1; D019204:GTP-Binding Proteins; D002945:Cisplatin