title: γ-Secretase-dependent cleavage of E-cadherin by staurosporine in breast cancer cells.
abstract: E-cadherin is a transmembrane protein that serves as a cell adhesion molecule component of the adherens junction. We previously showed that cadmium induced γ-secretase-dependent E-cadherin cleavage via oxidative stress. In this study, we report that staurosporine (STS)-induced apoptosis induces caspase-2 and/or -8-dependent E-cadherin cleavage. STS increased γ-secretase-dependent cleavage of E-cadherin in breast cancer cells through caspase activation. The ability of the γ-secretase inhibitor DAPT and the caspase inhibitor zVAD-FMK to block E-cadherin cleavage provided support for these results. The cleavage of E-cadherin was blocked by caspase-2 and -8 inhibitors. Immunofluorescence analysis confirmed that, along with the disappearance of E-cadherin staining at the cell surface, the E-cadherin cytoplasmic domain accumulated in the cytosol. In the presence of an inhibitor of γ-secretase or caspase, the cleavage of E-cadherin was partially blocked. Our findings suggest that activation of caspase-2/-8 stimulated the disruption of cadherin-mediated cell-cell contacts in apoptotic cells via γ-secretase activation.
authors.affiliation: Division of Brain Diseases, Center for Biomedical Sciences, Korea National Institute of Health, 187 Osongsaengmyeong2(i)-ro, Gangoe-myeon, Cheongwon-gun, Chungcheongbuk-do, Republic of Korea.
authors.forename: Chul Bae
authors.initials: CB
authors.lastname: Yoo
authors.forename: Sang-Moon
authors.initials: SM
authors.lastname: Yun
authors.forename: Chulman
authors.initials: C
authors.lastname: Jo
authors.forename: Young Ho
authors.initials: YH
authors.lastname: Koh
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism*; D053143:Caspase 2 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D061945:Caspase Inhibitors; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D008856:Microscopy, Fluorescence; D019311:Staurosporine / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D015820:Cadherins; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D053829:Amyloid Precursor Protein Secretases; D053143:Caspase 2; D053181:Caspase 8; D019311:Staurosporine