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

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 (2018) Differential Effects of Integrin αv Knockdown and Cilengitide on Sensitization of Triple-Negative Breast Cancer and Melanoma Cells to Microtubule Poisons. Molecular Pharmacology, 94 (6). pp. 1334-1351. ISSN 0026-895X

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Abstract

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.

Item Type:	Article
Uncontrolled Keywords:	integrins; integrin αv; integrin α4; integrin α3; integrin knockdown; cilengitide; PF-228; phospho FAK; sensitization; triple-negative breast cancer; melanoma cells; paclitaxel; vincristine; cisplatin; integrin switching; integrin crosstalk
Subjects:	NATURAL SCIENCES > Biology NATURAL SCIENCES > Biology > Biochemistry and Molecular Biology
Divisions:	Division of Molecular Biology
Projects:	Project title Project leader Project code Project type MOLEKULARNI MEHANIZMI POVEĆANJA OSJETLJIVOSTI NA PROTUTUMORSKE LIJEKOVE STANICA KARCINOMA DOJKE I MELANOMA ČOVJEKA UTIŠAVANJEM INTEGRINA-INSILCELL Andreja Ambriović Ristov IP-2013-11-2465 HRZZ Povećanje osjetljivosti stanica melanoma i glioma na alkilirajuće lijekove utišavanjem integrina αvβ3, αvβ5, α3β1 i α4β1 Andreja Ambriović Ristov UNSPECIFIED The bilateral program Deutscher Akademischer Austausch Dienst Povećanje transdukcije adenovirusnih vektora i otpornost stanica na citostatike- Andreja Ambriović Ristov 098-0982913-2850 MZOS
Depositing User:	Ana Tadijan
Date Deposited:	26 Nov 2019 11:47
URI:	http://fulir.irb.hr/id/eprint/5108
DOI:	10.1124/mol.118.113027

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