Protein kinase C mediates cisplatin-induced loss of adherens junctions followed by apoptosis of renal proximal tubular epithelial cells

The Journal of Pharmacology and Experimental Therapeutics
Raoef ImamdiBob van de Water

Abstract

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 Go6983 [2-[1-(3-dimethylaminopropyl)-5-methoxyindol-3-yl]-3-(1H-indol-3-yl) maleimide], but not by Go6976 [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 beta-catenin in association with PKC-mediated phosphorylation of the actincapping protein adducin. These events preceded and were independent of caspase activation. beta-C...Continue Reading

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Citations

Jan 30, 2010·Journal of the American Society of Nephrology : JASN·Maria Dolores Sanchez-NiñoAlberto Ortiz
Nov 9, 2006·Experimental Lung Research·Rebecca E SlagerTodd A Wyatt
Jul 10, 2013·Annals of Neurology·Michael C KruerHenry Houlden
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Jan 29, 2009·Journal of Cell Science·Chien-Lin Chen, Hong-Chen Chen

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