engleski

Differential effects of integrin αV knockdown and cilengitide on sensitisation of triple-negative breast cancer and melanoma cells to microtubule poisons

Low survival rates of patients with metastatic triple negative breast cancer (TNBC) and melanoma, in which current therapies are ineffective, emphasize the need for new therapeutic approaches. Integrin signalling regulates proliferation, migration, metastasis and cell death and has been suggested as a possible target in antitumor therapy. Although seen as a promising target when combined with chemotherapy, recent data on integrin β1 have shown that its inactivation increases metastatic potential due to the compensatory upregulation of other integrin subunits. Therefore, the aim of this study was to investigate the potential of integrin subunits αv, α3, or α4 knockdown in increasing sensitivity in seven TNBC (MDA-MB-231, -468 and -436) and melanoma (MDA-MB-435S, RPMI-7951, MeWo and A375) cell lines to cisplatin, microtubule poisons paclitaxel (PTX) and vincristine (VCR), and mitigating metastatic potential. Experiments performed in integrin αvβ1 negative melanoma cell line MDA-MB-435S identified integrin subunit αv as a target whose knockdown increases sensitivity to vincristine or paclitaxel, and decreases migration and invasion. In MDA-MB-435S cell line we also identified a phenomenon in which change in expression of one integrin subunit changes the expression of other integrin/s, leading to an unpredictable influence on sensitivity to anticancer drugs and cell migration referred to as the integrin switching effect. The contribution of integrins αv versus integrins αvβ3/β5 was also assessed in a panel of six TNBC and melanoma cell lines by the combined action of αv-specific siRNA or αvβ3/β5 inhibitor cilengitide with paclitaxel. Knockdown of integrin αv in combination with VCR and PTX resulted in beneficial effect in all three TNBC cell lines, while in melanoma cell lines we observed beneficial effect in only one cell line out of three. Interestingly, cilengitide-driven inactivation of integrin heterodimers αvβ3 and αvβ5 showed beneficial effect in combination with PTX in five out of seven TNBC and melanoma cell lines, although in a different set of cells as compared to integrin αv knockdown. Our results suggest that for TNBC the knockdown of integrin αv in combination with paclitaxel presents a better therapeutic option than cilengitide, and simultaneously decreases migration and invasion. However, in melanoma neither of these combinations is advisable because decreased sensitivity to paclitaxel was observed.

melanoma ; breast cancer ; integrins ; cilengitide ; siRNA ; resistance

Nikolina Stojanović and Ana Dekanić contributed equally to this work.