Differential Effects of Integrin αv Knockdown and Cilengitide on Sensitization of Triple-Negative Breast Cancer and Melanoma Cells to Microtubule Poisons

• Published in: Molecular pharmacology 2018-12, Vol.94 (6), p.1334-1351
• Main Authors: Stojanović, Nikolina, Dekanić, Ana, Paradžik, Mladen, Majhen, Dragomira, Ferenčak, Krešimir, Ruščić, Jelena, Bardak, Irena, Supina, Christine, Tomicic, Maja T., Christmann, Markus, Osmak, Maja, Ambriović-Ristov, Andreja
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; Cell Line, Tumor; Cell Movement - drug effects; Cell Movement - genetics; Female; Gene Expression Regulation, Neoplastic - drug effects; Humans; Integrin alphaV - genetics; Melanoma - drug therapy; Microtubules - drug effects; Paclitaxel - pharmacology; Poisons - pharmacology; Snake Venoms - pharmacology; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - genetics
• ISSN: 0026-895X; 1521-0111
• DOI: 10.1124/mol.118.113027

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 owing to the compensatory upregulation of other integrin subunits. Consequently, we analyzed the potential of integrin subunits αv, α3, or α4 as targets for improved therapy in seven TNBC and melanoma cell lines. Experiments performed in an 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 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 αv versus integrins αvβ3/β5 was assessed by the combined action of αv-specific small interfering RNA 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 a combination of cilengitide with paclitaxel; however, in melanoma, neither of these combinations is advisable because a decreased sensitivity to paclitaxel was observed.