Endoplasmic reticulum stress-associated caspase 12 mediates cisplatin-induced LLC-PK1 cell apoptosis.
Reactive oxygen metabolites are important mediators in cisplatin-induced apoptosis in renal tubular epithelial cells (LLC-PK1). Mitochondria have been implicated to play a principal role in cisplatin-induced apoptosis. Caspase 12, an endoplasmic reticulum (ER)-specific caspase, participates in apoptosis under ER stress. Cytochrome P450 system is crucial to the generation of reactive oxygen metabolites and is present at high concentration in the ER. The direct role of caspase 12 in any model of renal injury has not previously been described. In this study, cleavage of procaspase 12 preceded that of caspases 3 and 9 after cisplatin treatment of LLC-PK1 cells. The active form of caspase 8 was not detected throughout the course of study. Preincubation of the LLC-PK1 cells with the caspase 9 inhibitor did not attenuate caspase 3 activation and provided no significant protection. Caspase 3 inhibitor provided only modest protection against cisplatin-induced apoptosis. LLC-PK1 cells that were transfected with anti-caspase 12 antibody significantly attenuated cisplatin-induced apoptosis. Taken together, these data indicate that caspase 12 plays a pivotal role in cisplatin-induced apoptosis. It is proposed that the oxidative stress that results from the interaction of cisplatin with the ER cytochrome P450 leads to activation of procaspase 12, resulting in apoptosis.
Liu
Hua
H
Department of Pediatrics, Division of Nephrology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216-4505, USA.
Baliga
Radhakrishna
R
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D053454:Caspase 12; D020169:Caspases / Q000502:physiology*; D002945:Cisplatin / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System; D004721:Endoplasmic Reticulum / Q000502:physiology; D006801:Humans; D018374:LLC-PK1 Cells; D018384:Oxidative Stress / Q000502:physiology; D017382:Reactive Oxygen Species
D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D003577:Cytochrome P-450 Enzyme System; C506444:CASP12 protein, human; D053454:Caspase 12; D020169:Caspases; D002945:Cisplatin