engleski

Chemosensitisation of human breast carcinoma cell line MDA-MB-435S to vincristine and paclitaxel by silencing integrin αv or α4

Integrin signalling regulates numerous cellular processes including proliferation, migration, metastasis, cancer-induced angiogenesis, and cell death. The aim of this study was to investigate the role of integrins αvß3, αvß5, α3ß1 and α4ß1 expressed on MDA-MB-435S cells in sensitivity to the drugs frequently used in breast cancer therapy: vincristine, paclitaxel, doxorubicin, camptothecin and cisplatin. While decreased expression of integrins αvß3, αvß5 or α3ß1, achieved by ß3, ß5, αv or α3- specific siRNA transfection, reduced sensitivity of MDA-MB-435S cells to cisplatin, no change was observed in MDA-MB-435S cells upon knockdown of α4ß1 using α4 siRNA transfection. Conversely, decreased expression of integrins αvß5 or α4ß1 upon integrin subunit ß5, αv or α4 siRNA transfection sensitized MDA-MB-435S cells to vincristine or paclitaxel, but there was no change in cell survival upon knockdown of integrins α3ß1 or αvß3 upon α3 or ß3 siRNA transfection. The cytotoxic activity of camptothecin and doxorubicin was not altered upon transfection of any of analysed siRNAs. The down-regulation of integrins αvß3 and αvß5 achieved by αv siRNA transfection strongly decrease migration, amount of stress fibers and focal adhesions, whereas the down-regulation of integrin α4ß1 upon α4 siRNA transfection moderately increased cell migration with simultaneous slight increase in amount of stress fibers and focal adhesions. We suggest that transfection of at least some breast carcinoma cells with integrin αv siRNA could enhance activity of vincristine or paclitaxel and simultaneously inhibit their metastatic potential. These new insights should be useful when devising strategies for more efficient treatment.

integrins ; resistance ; tumor cells ; anticancer drugs

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