engleski

Resistance of human laryngeal carcinoma cells to cisplatin and altered cell adhesion

Resistance of tumor cells to chemotherapy critically limits the outcome of cancer treatment. It may occur at several levels. Recently, a new phenomenon of drug resistance has been discovered, called cell adhesion-mediated drug resistance. We have developed cisplatin resistant human laryngeal carcinoma CA3ST cells, that exhibited consistent differences in cell adhesion as compared to their parental HEp2 cells. The aim of the present study was to examine molecular basis for this phenomenon. The cell adhesion to component of extracellular matrix is mediated by integrins. Using semiquantitative RT-PCR analysis, in resistant cells only up-regulation of alphavbeta3 integrin was found, that was additionally confirmed by flow cytometry. The integrin expression plasmid pcDNA3beta3 was transfected into HEp2 cells. Derived cell lines expressing different amounts of alphavbeta3 integrin have been isolated and screened by flow cytometry for integrin expression. Isolated clones that exhibit alphavbeta3 integrin were resistant to cisplatin. Cell-cell adhesion (predominantly mediated by cadherin-catenin complexes) may have an important role in cell-resistance as well. Western blot analysis of expression of several proteins from this complex reveals alterations only in expression of plakoglobin (strongly downregulated), and b-catenin (upregulated). Lower plakoglobin expression was detected by semiquantitative RT-PCR as well, while equal expression of b-catenin mRNA was determined as compared to their parental HEp-2 cells. Coimmunoprecipitation of cadherin-catenin complexes suggests that increased expression of b-catenin in cisplatin resistant variants results from its stabilisation through interaction with N-cadherin. In conclusion, alteration in cell adhesion may contribute to resistance of laryngeal carcinoma cells to cisplatin. These findings may have important therapeutic implications. Further, upregulation of alphavbeta3 integrin in cisplatin resistant CA3ST cells caused increased adenoviral transduction (Ambriović-Ristov et al., Int J Cancer ; 110(2004) 660-667), suggesting that drug resistant cells could be a better target for adenovirus gene therapy than the parental tumor cells.

cisplatin; drug-resistance; cell adhesion

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