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TOXICOLOGY

Protein Kinase C Mediates Cisplatin-Induced Loss of Adherens Junctions Followed by Apoptosis of Renal Proximal Tubular Epithelial Cells

Division of Toxicology, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands

Cisplatin is a commonly used antitumor agent in the treatment of various human cancers, with nephrotoxicity as a major side effect. Cisplatin causes the loss of cell-cell contacts of renal proximal tubular epithelial cells prior to the onset of apoptosis. We studied the involvement of protein kinase C in these events in the renal epithelial cell line LLC-PK1. Cisplatin caused apoptosis in LLC-PK1 cells, which was directly related to the activation of caspase-3 and DNA fragmentation. Apoptosis was almost completely inhibited by the protein kinase C inhibitors bisindolylmaleimide (Bis) I and Gö6983 [2-[1-(3-dimethylaminopropyl)-5-methoxyindol-3-yl]-3-(1H-indol-3-yl) maleimide], but not by Gö6976 [12-(2-cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo(2,3-a)pyrrolo(3,4-c)-carbazole]. Also, in primary cultured rat renal proximal tubular cells, inhibition of protein kinase C (PKC) inhibited apoptosis. Cisplatin also caused the early loss of cell-cell adhesions, which was associated with the altered localization of the adherens junction-associated protein -catenin in association with PKC-mediated phosphorylation of the actincapping protein adducin. These events preceded and were independent of caspase activation. -Catenin did not dissociate from E-cadherin. Cisplatin-induced loss of cell-cell contacts was associated with the increased formation of F-actin stress fibers, which was inhibited by Bis I and Gö6983 as well as dominant-negative PKC-. Also, the loss of cell-cell adhesions by cisplatin was prevented by Bis I and Gö6983. Activation of protein kinase C with phorbol esters promoted cisplatin-induced loss of cell-cell adhesions as well as apoptosis. In conclusion, the combined data fit a model whereby protein kinase C mediates the cisplatin-induced loss of cellular interactions. Such a loss of these interactions has a role in the onset of apoptosis.

Address correspondence to: Dr. B. van de Water, Division of Toxicology, Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratoria, P.O. Box 9502, 2300 RA Leiden, The Netherlands. E-mail: b.water{at}lacdr.leidenuniv.nl

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