Cisplatin-induced apoptosis in p53-deficient renal cells via the intrinsic mitochondrial pathway.
Nephrotoxicity is the major limiting factor for the use of cisplatin in cancer therapy. Recent studies have demonstrated an important role for p53 in cisplatin-induced renal injury. Nevertheless, pharmacological and genetic blockade of p53 only provides partial renoprotective effects, suggesting the presence of p53-independent injury mechanisms. To understand the p53-independent mechanisms, we have now examined cisplatin-induced apoptosis in p53-deficient kidney cells. We show that cisplatin could induce Bax activation, cytochrome c release, and apoptosis in primary cultures of p53-deficient renal tubular cells, albeit at a level that was lower than in the wild-type cells. Cisplatin could also induce typical apoptosis in p53-deficient baby mouse kidney (BMK) cells. The apoptosis was caspase dependent and could be completely blocked by general caspase inhibitors. Bax and Bak, two key molecules in the mitochondrial pathway of apoptosis, were interdependently activated by cisplatin, with Bax translocation to and Bax/Bak oligomerization in mitochondria, leading to cytochrome c release. Importantly, cytochrome c release and apoptosis were diminished in Bax/Bak single or double-knockout BMK cells. Furthermore, overexpression of Bcl-2 could ameliorate cisplatin-induced cytochrome c release and apoptosis. Together, the results have demonstrated a p53-independent mechanism of cisplatin nephrotoxicity that involves the mitochondrial pathway of apoptosis.
Jiang
Man
M
Department of Cellular Biology and Anatomy, Medical College of Georgia, 1459 Laney Walker Blvd., Augusta, GA 30912, USA.
Wang
Cong-Yi
CY
Huang
Shuang
S
Yang
Tianxin
T
Dong
Zheng
Z
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002945:Cisplatin / Q000633:toxicity*; D045304:Cytochromes c / Q000378:metabolism; D007668:Kidney / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D008928:Mitochondria / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D000970:Antineoplastic Agents; C494773:Bak1 protein, mouse; C494827:Bax protein, mouse; D061945:Caspase Inhibitors; D016159:Tumor Suppressor Protein p53; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; D020169:Caspases; D002945:Cisplatin