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The roles of caspase-3 and bcl-2 in chemically-induced apoptosis but not necrosis of renal epithelial cells

Oncogene volume 18, pages 6505–6512 (1999)Cite this article

Abstract

The kidney is a target for toxicants including cisplatin and S-(1,2-dichlorovinyl)-L-cysteine (DCVC), a metabolite of the environmental contaminant, trichloroethylene. Necrosis is well characterized in kidney cells, but pathways leading to apoptosis are less clear. Cysteine conjugates are useful toxicants because they induce either necrosis or apoptosis depending on chemical structure or antioxidant status. Herein, we show that in the renal epithelial cell line LLC-PK1, activation of caspase-3 (CPP32/Yama/apopain) is crucial for apoptosis, but not necrosis. Apoptosis was blocked by zVAD.fmk, and partially by a cathepsin inhibitor. Caspase-3 activity and cleavage of poly(ADP-ribose) polymerase (PARP) was detected only during apoptosis. S-(1,1,2,2-Tetrafluoroethyl)-L-cysteine (TFEC), a metabolite of tetrafluoroethylene, kills cells only by necrosis, and did not activate caspases under any conditions. Apoptosis and activation of caspase-3 by cisplatin, but not DCVC, was prevented by bcl-2. Thus, caspase-3 activation by bcl-2-dependent and -independent mechanisms is a terminal event in chemical-apoptosis of renal epithelial cells.

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Abbreviations

DCVC:

S-(1,2-dichlorovinyl)-L-cysteine

DMEM:

Dulbecco's modified Eagles's medium

DPPD:

N,N′-phenyl-p-phenylenediamine

LDH:

lactate dehydrogenase

PARP:

poly(ADP-ribose) polymerase

pkBcl-2:

cells transfected with a bcl-2 expression vector and selected for neomycin resistance

pkNEO:

cells transfected with a neomycin resistance marker only

TFEC:

S-(1,1,2,2-tetrafluoroethyl)-L-cysteine

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Acknowledgements

These studies were supported by Public Health Service Grants DK46267 and ES07847 to JL Stevens and a Talent Stipend from the Dutch Organization for Scientific Research to B van de Water. The authors thank Dr Don Nicholson for providing the anti-caspase-3 antibody, Sal Morana for reading the manuscript. We also thank JoEllen Welsh and Manjula Donepudi for assistance with the flow cytometery.

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Authors and Affiliations

  1. Department of Pathology, College of Medicine, A249 Medical Alumni Building, University of Vermont, Burlington, 05405, VT, USA

    James L Stevens

  2. Adirondack Biomedical Research Institute, Lake Placid, New York, 12946, NY, USA

    Yi Zhan, Bob van de Water, Yuping Wang & James L Stevens

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Zhan, Y., van de Water, B., Wang, Y. et al. The roles of caspase-3 and bcl-2 in chemically-induced apoptosis but not necrosis of renal epithelial cells. Oncogene 18, 6505–6512 (1999). https://doi.org/10.1038/sj.onc.1203060

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