Integrin αvβ3 Expression in Tongue Squamous Carcinoma Cells Cal27 Confers Anticancer Drug Resistance Through Loss of pSrc(Y418)

Stojanović, Nikolina; Brozović, Anamaria; Majhen, Dragomira; Herak Bosnar, Maja; Fritz, Gerhard; Osmak, Maja; Ambriović-Ristov, Andreja (2016) Integrin αvβ3 Expression in Tongue Squamous Carcinoma Cells Cal27 Confers Anticancer Drug Resistance Through Loss of pSrc(Y418). BBA - Molecular Cell Research, 1863 (8). pp. 1969-1978. ISSN 0167-4889

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Abstract

Integrins play key roles in the regulation of tumor cell adhesion, migration, invasion and sensitivity to anticancer drugs. In the present study we investigate the mechanism of resistance of tongue squamous carcinoma cells Cal27 with de novo integrin αvβ3 expression to anticancer drugs. Cal27-derived cell clones, obtained by transfection of plasmid containing integrin subunit β3 cDNA, as compared to control cells demonstrate: expression of integrin αvβ3 ; increased expression of integrin αvβ5 ; increased adhesion to fibronectin and vitronectin ; resistance to cisplatin, mitomycin C, doxorubicin and 5-fluorouracil ; increased amount of integrin-linked kinase (ILK) and decreased amounts of non-receptor tyrosine kinase (Src) and pSrc(Y418). Knockdown of ILK and integrin β5 in cells expressing integrin αvβ3 ruled out their involvement in drug resistance. Opposite, Src knockdown in Cal27 cells which led to a reduction in pSrc(Y418), as well as treatment with the pSrc(Y418) inhibitors dasatinib and PP2, conferred resistance to all four anticancer drugs, indicating that the loss of pSrc(Y418) is responsible for the observed effect. We identified differential integrin signaling between Cal27 and integrin αvβ3-expressing cells. In Cal27 cells integrin αv heterodimers signal through pSrc(Y418) while this is not the case in integrin αvβ3-expressing cells. Finally, we show that dasatinib counteracts the effect of cisplatin in two additional head and neck squamous cell carcinoma (HNSCC) cell lines Cal33 and Detroit562. Our results suggest that pSrc(Y418) inhibitors, potential drugs for cancer therapy, may reduce therapeutic efficacy if combined with chemotherapeutics, and might not be recommended for HNSCC treatment.

Item Type:	Article
Additional Information:	The work was supported by the grant received from the Ministry of Science, Education and Sports of the Republic of Croatia (Project numbers 098-0982913-2850 and 098-0982913-2748), the Croatian-German Bilateral Grant (MZOS-DAAD) to GF and MO and by FP7-REGPOT-2012-2013-1, Grant Agreement Number 316289 - InnoMol.
Uncontrolled Keywords:	integrin αvβ3 ; drug resistance ; Src ; Src inhibitors ; HNSCC cells
Subjects:	NATURAL SCIENCES > Biology NATURAL SCIENCES > Biology > Biochemistry and Molecular Biology
Divisions:	Division of Molecular Biology Division of Molecular Medicine
Projects:	Project title Project leader Project code Project type Povećanje transdukcije adenovirusnih vektora i otpornost stanica na citostatike- Andreja Ambriović Ristov 098-0982913-2850 MZOS Stanični odgovor na citotoksične spojeve i razvoj otpornosti- Maja Osmak 098-0982913-2748 MZOS Enhancement of the Innovation Potential in SEE through new Molecular Solutions in Research and Development-INNOMOL UNSPECIFIED 316289 EK
Depositing User:	Nikolina Stojanović
Date Deposited:	27 Nov 2017 16:14
URI:	http://fulir.irb.hr/id/eprint/3688
DOI:	10.1016/j.bbamcr.2016.04.019

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