title: Altered cell-cell adhesion in cisplatin-resistant human carcinoma cells: a link between beta-catenin/plakoglobin ratio and cisplatin resistance.
abstract: Acquired resistance to cisplatin represents a major obstacle to successful chemotherapy. We have developed cisplatin-resistant CA3(ST) and CK2 cells, which exhibited altered formation of cell-cell junctions compared to their parental cisplatin-sensitive human laryngeal carcinoma HEp-2 cells. Although cell-cell adhesion can induce antiapoptotic signaling, there is contradictory evidence considering the significance of cadherin-catenin complex in cellular response to cisplatin. Therefore, we analyzed junctional proteins in this model of cisplatin resistance. In both cisplatin-resistant sublines plakoglobin expression was decreased, while beta-catenin expression was increased, at cell-cell junctions. Although cisplatin-resistant cells showed decreased plakoglobin mRNA, they retained equal expression of beta-catenin mRNA as parental cells. Immunoprecipitation of cadherin-catenin complex established that upregulation of beta-catenin results from its stabilization through interaction with N-cadherin. Furthermore, beta-catenin upregulation was closely associated with cisplatin exposure, since cisplatin-resistant HeLa subline also had increased beta-catenin, while vincristine-resistant HEp-2 subline did not upregulate beta-catenin. However, single cisplatin treatment of HEp-2 cells did not induce beta-catenin upregulation, nor plakoglobin mRNA downregulation, suggesting that the alteration in catenin ratio is a late event, which requires repeated cisplatin exposure. Finally, we overexpressed plakoglobin in CA3(ST) cells and selected several clones that established the pattern of plakoglobin/beta-catenin expression found in HEp-2 cells. However, none of the clones restored sensitivity to cisplatin. Thus, it appears that beta-catenin and plakoglobin are not involved in the resistance development, implying that the observed alterations are an outcome of a slowly generating process, which is presumably a secondary event of vital cellular response triggered by cisplatin toxicity.
authors.affiliation: Laboratory for Genotoxic Agents, Division of Molecular Biology, Ruether Bosković Institute, Bijenicka 54, 10000 Zagreb, Croatia.
authors.forename: Tamara
authors.initials: T
authors.lastname: Cimbora-Zovko
authors.forename: Andreja
authors.initials: A
authors.lastname: Ambriović-Ristov
authors.forename: Jadranka
authors.initials: J
authors.lastname: Loncarek
authors.forename: Maja
authors.initials: M
authors.lastname: Osmak
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D051180:Desmoplakins / Q000235:genetics*; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007822:Laryngeal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D014162:Transfection; D051176:beta Catenin / Q000235:genetics*; D051185:gamma Catenin
chemical_list: D000970:Antineoplastic Agents; D015820:Cadherins; D051180:Desmoplakins; C495292:JUP protein, human; D012333:RNA, Messenger; D051176:beta Catenin; D051185:gamma Catenin; D002945:Cisplatin