11179455

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3

Cell adhesion is important in the regulation of cell proliferation, migration, survival, and apoptosis. The major components of cell adhesion are the cadherin family of proteins, alpha-, beta- and gamma-catenins, and cytoskeletons. In addition, beta-catenin, when associated with adenomatous polyposis coli (APC) protein, an oncosuppressor, is implicated in the regulation of beta-catenin/APC-related signaling pathways. To examine the correlation between impairment of cell adhesion events and apoptosis, we used human non-small-cell lung cancer H460 and H520 cell lines as models to determine whether paclitaxel-induced apoptosis is associated with disruption of the components of cell adhesion and their functions. Paclitaxel treatment resulted in cells rounding up and losing contact with their neighboring cells, suggesting that the drug does indeed affect cell adhesion and related events. Western blot analysis revealed that paclitaxel caused a time- and concentration-dependent cleavage of beta-catenin, gamma-catenin, and APC protein, but not alpha-catenin or E-cadherin. These cleavages of beta-catenin and gamma-catenin were apoptosis-dependent, not mitosis-dependent. Paclitaxel treatment led to the proteolysis and activation of caspase-3 and -7, but not caspase-1. Furthermore, paclitaxel-induced apoptosis and cleavage of beta-catenin and gamma-catenin were inhibited by the pan-caspase inhibitor Z-VAD-FMK and partially inhibited by the caspase-3 inhibitor Z-DEVD-FMK but were not affected by the caspase-1 inhibitor AC-YVAD-CMK. Although the pan-caspase inhibitor blocked the cleavage of beta-catenin as well as DNA fragmentation, it did not affect paclitaxel-induced M-phase arrest and only partially prevented cell-growth inhibition. Biochemical studies revealed that cleaved beta-catenin was detected only in the Triton X-100 insoluble fraction, suggesting that it might localize in nuclear and/or membrane structures. Interestingly, the paclitaxel-induced beta-catenin fragment lost its ability to bind to E-cadherin, alpha-catenin, or APC protein and to serve as a substrate for tyrosine kinase. All our data demonstrate that the caspase-mediated cleavage of beta-catenin, gamma-catenin, and APC protein might contribute to paclitaxel-induced apoptosis.

eng

IM

MEDLINE

0026-895X

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593-603

pubmed-meshheading:11179455-Adenomatous Polyposis Coli Protein, pubmed-meshheading:11179455-Antineoplastic Agents, Phytogenic, pubmed-meshheading:11179455-Apoptosis, pubmed-meshheading:11179455-Caspase 3, pubmed-meshheading:11179455-Caspase 7, pubmed-meshheading:11179455-Caspases, pubmed-meshheading:11179455-Cell Adhesion, pubmed-meshheading:11179455-Cytoskeletal Proteins, pubmed-meshheading:11179455-Desmoplakins, pubmed-meshheading:11179455-Enzyme Activation, pubmed-meshheading:11179455-G2 Phase, pubmed-meshheading:11179455-Humans, pubmed-meshheading:11179455-Mitosis, pubmed-meshheading:11179455-Paclitaxel, pubmed-meshheading:11179455-Phosphorylation, pubmed-meshheading:11179455-Subcellular Fractions, pubmed-meshheading:11179455-Trans-Activators, pubmed-meshheading:11179455-Tumor Cells, Cultured, pubmed-meshheading:11179455-beta Catenin, pubmed-meshheading:11179455-gamma Catenin

Disruption of cell adhesion and caspase-mediated proteolysis of beta- and gamma-catenins and APC protein in paclitaxel-induced apoptosis.

Journal Article, Research Support, U.S. Gov't, P.H.S.