Naslov
Altered cell-cell adhesion in cisplatin-resistant human carcinoma cells: A link between β -catenin/plakoglobin ratio and cisplatin resistance

Autori
Čimbora-Zovko, Tamara ; Ambriović-Ristov, Andreja ; Lončarek, Jadranka ; Osmak, Maja

Izvornik
European Journal of Pharmacology (0014-2999) 558 (2007), 1-3; 27-36

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
cisplatin; drug-resistance; beta-catenin; plakoglobin; cell adhesion

Sažetak
Acquired resistance to cisplatin represents a major obstacle to successful chemotherapy. We have developed cisplatin-resistant CA3ST and CK2 cells, which exhibited altered formation of cell-cell junctions comparing 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 b-catenin expression was increased, at cell-cell junctions. Although cisplatin-resistant cells showed decreased plakoglobin mRNA, they retained equal expression of b-catenin mRNA as parental cells. Immunoprecipitation of cadherin-catenin complex established that upregulation of b-catenin results from its stabilization through interaction with N-cadherin. Furthermore, b-catenin upregulation was closely associated with cisplatin exposure, since cisplatin-resistant HeLa subline also had increased b-catenin, while vincristine-resistant HEp-2 subline did not upregulate b-catenin. However, single cisplatin treatment of HEp-2 cells did not induce b-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 CA3ST cells and selected several clones that established the pattern of plakoglobin/b-catenin expression found in HEp-2 cells. However, none of the clones restored sensitivity to cisplatin. Thus, it appears that β -catenin and plakoglobin are not involved in the resistance development, implying that the observed alterations are an outcome of slowly generating process, which is presumably a secondary event of vital cellular response triggered by cisplatin toxicity.

Izvorni jezik
Engleski

Znanstvena područja
Biologija

POVEZANOST RADA