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 β1 appears to be a promising target when combined with chemotherapy, but recent data have shown that its inactivation increases metastatic potential due to the compensatory upregulation of other integrin subunits. Consequently, we decided to analyze the potential of integrin subunits αv, α3, or α4 as targets for improved therapy in seven TNBC and melanoma cell lines. Experiments performed in integrin αvβ1 negative melanoma cell line MDA-MB-435S showed that knockdown of integrin subunit αv increased sensitivity to microtubule poisons vincristine or paclitaxel, and decreased 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. In a panel of six TNBC and melanoma cell lines the contribution of integrins αv versus integrins αvβ3/β5 was assessed by the combined action of αv-specific siRNA or αvβ3/β5 inhibitor cilengitide with paclitaxel. Our results suggest that, for TNBC, knockdown of integrin αv in combination with paclitaxel presents a better therapeutic option than combination of cilengitide with paclitaxel. However, in melanoma neither of these combinations is advisable because decreased sensitivity to paclitaxel was observed.

Breast cancer ; Cancer chemotherapy ; Cell migration ; Focal adhesion kinase (FAK) ; Integrins ; Skin cancer ; siRNA/shRNA

Nikolina Stojanović and Ana Dekanić contributed equally to this work. Rad je priključen i projektu: Povećanje osjetljivosti stanica melanoma i glioma na alkilirajuće lijekove utišavanjem integrina αvβ3, αvβ5, α3β1 i α4β1 ; voditeljica: Andreja Ambriović Ristov ; The bilateral program Deutscher Akademischer Austausch Dienst