engleski

Knockdown of integrin αv in human triple-negative breast carcinoma cell lines alters sensitivity to anticancer drugs and inhibits migration

Triple-negative breast cancer (TNBC) do not express estrogen receptor, progesterone receptor or human epidermal growth factor receptor 2 (Her2) and therefore, chemotherapy remains the mainstay of treatment. Integrin signalling regulates numerous processes in tumor cells including cell adhesion, migration, invasion and survival. Integrins are used as prognostic indicators in breast cancer. The aim of this study was to investigate whether knockdown of integrin αv could increase sensitivity to vincristine, paclitaxel and cisplatin, and inhibit cell migration, which is a prerequisite for cell invasion. Expression of integrin subunit αv and integrin heterodimers αvβ3 and αvβ5 in metastatic MDA-MB-435S MDA-MB-231, MDA-MB-468 and MDA-MB-436 cells was measured by flow cytometry. All cells expressed αv integrin subunit. Integrin heterodimer αvβ5 was highly expressed in all cells except MDA-MB-436. Integrin heterodimer αvβ3 was highly expressed in MDA-MB-435S and MDA-MB-231, while a lower amount was found in MDA-MB-468 while MDA-MB-436 cells were found to be αvβ3 negative. Decreased expression of integrin αv, achieved by αv-specific siRNA transfection, increased sensitivity of MDA-MB-435S, MDA-MB-231 and MDA-MB-468 cells to vincristine and increased sensitivity of MDA-MB-435S and MDA-MB-231 cells to paclitaxel. Conversely, decreased expression of integrin αv decreased sensitivity to cisplatin in MDA-MB-435S and MDA-MB-468 cells but increased sensitivity in MDA-MB-468 cells. Upon integrin αv knockdown in MDA-MB-436 cell line no alteration in sensitivity to any of the abovementioned drugs was observed. The in vitro transwell migration assay in MDA-MB-435S, MDA-MB-231 and MDA-MB-468 cells showed that knockdown of integrin αv strongly decreases cell migration. The most dramatic effect was observed in MDA-MB-435S and MDA-MB-468 cells. Immunofluorescence analysing in MDA-MB-435s cells showed disappearance of actin stress fibers and focal adhesion marker protein phospho-paxillin (Y113). We suggest that transfection of at least some TNBC cells with integrin αv siRNA could enhance activity of vincristine and paclitaxel, and simultaneously inhibit their metastatic potential. These new insights should be useful when devising strategies for more efficient TNBC treatment.

integrins ; silencing ; tumor cell resistance ; anticancer drugs ; migration

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