Altered cell-cell adhesion in cisplatin-resistant human carcinoma cells: a link between beta-catenin/plakoglobin ratio and cisplatin resistance.

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.