Differential Effects of Integrinαv Knockdown and Cilengitide on Sensitization 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 β 1 appears to be a promising target when combined with chemotherapy, but recent data have shown that its inactivation increases metastatic potential owing to the compensatory upregulation of other integrin subunits. Consequently, we analyzed the potential of integrin subunits α v, α 3, or α 4 as targets for improved therapy in seven TNBC and melanoma cell lines. Experiments performed in an integrin α v β 1-negative melanoma cell line, MDA-MB-435S, showed that knockdown of integrin subuni α v increased sensitivity to microtubule poisons vincristine or paclitaxel and decreased migration and invasion. In the MDA-MB-435S cell line, we also identified a phenomenon in which change in the expression of one integrin subunit changes the expression of other integrins, 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 TNBCs and melanoma cell lines, the contribution of integrins α v versus integrins α v β 3/ β 5 was assessed by the combined action of α v-specific small interfering RNA or α v β 3/ β 5 inhibitor cilengitide with paclitaxel. Our results suggest that, for TNBC, knockdown of integrin α v in combination with paclitaxel presents a better therapeutic option than a combination of cilengitide with paclitaxel; however, in melanoma, neither of these combinations is advisable because a decreased sensitivity to paclitaxel was observed.