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Asbestos-Induced Apoptosis Is Protein Kinase C-Dependent

Departments of Pathology and Pharmacology, University of Vermont College of Medicine, Burlington, Vermont

Address correspondence to: Brooke T. Mossman, Ph.D., Department of Pathology, University of Vermont College of Medicine, 89 Beaumont Avenue, Burlington, VT 05405. E-mail: brooke.mossman{at}uvm.edu

Alveolar epithelial and mesothelial cells undergo apoptosis in response to asbestos, a phenomenon that may be important in injury and/or initiation of compensatory proliferation. Here, we report a functional role of protein kinase (PKC) in apoptosis by crocidolite asbestos. We first show that asbestos increases the kinase activity of PKC in alveolar type II epithelial cells (C10 line) and causes its translocation to mitochondria, events associated with caspase-9 cleavage and apoptosis as detected by the Apostain technique. Pretreatment of C10 cells with rottlerin (Rot), a PKC–selective inhibitor, before addition of asbestos prevented cleavage of caspase-9 and blocked the appearance of apoptotic cells. Asbestos-induced apoptosis also was inhibited in cells stably expressing a dominant-negative kinase-deficient mutant of PKC (dnPKC), but not dnPKC. Activities of PKC and PKC increased after exposure to asbestos, but neither isoform migrated to mitochondria. A general inhibitor of PKCs, bisindolylmaleimide I, had no effect on asbestos-induced apoptosis. Hydrogen peroxide (H₂O₂) induced activation of PKCs , , , and , translocation of PKC to mitochondria, and caspase-9 cleavage. However, H₂O₂-induced apoptosis was not inhibited by cell lines stably expressing either dnPKC or dnPKC, suggesting that activation of PKC has a distinct role in the development of asbestos-induced apoptosis.

Abbreviations: bisindolymaleimide, Bis • bovine serum albumin, BSA • diacylglycerol, DAG • dominant negative PKC, dnPKC • fetal bovine serum, FBS • hydrogen peroxide, H₂O₂ • hemagglutinin, HA • mitogen-activated protein kinase, MAPK • phosphate-buffered saline, PBS • PBS containing 0.1% Tween-20, PBST • phorbol dibutyrate, PDBu • protein kinase C, PKC • rottlerin, Rot • room temperature, RT • Tris-buffered saline, TBS

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