Integrin αvβ3 expression in tongue squamous carcinoma cells Cal27 confers anticancer drug resistance through loss of pSrc(Y418).
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 migration and invasion, 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.
Laboratory for Cell Biology and Signalling, Division of Molecular Biology, Ruđer Bošković Institute, Bijenička 54, 10000 Zagreb, Croatia.
Nikolina
N
Stojanović
Laboratory for Cell Biology and Signalling, Division of Molecular Biology, Ruđer Bošković Institute, Bijenička 54, 10000 Zagreb, Croatia.
Anamaria
A
Brozovic
Laboratory for Cell Biology and Signalling, Division of Molecular Biology, Ruđer Bošković Institute, Bijenička 54, 10000 Zagreb, Croatia.
Dragomira
D
Majhen
Laboratory for Protein Dynamics, Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička 54, 10000 Zagreb, Croatia.
Maja Herak
MH
Bosnar
Heinrich Heine University Düsseldorf, Medical Faculty, Institute of Toxicology, Universitätsstrasse 1, 40225 Düsseldorf, Germany.
Gerhard
G
Fritz
Laboratory for Cell Biology and Signalling, Division of Molecular Biology, Ruđer Bošković Institute, Bijenička 54, 10000 Zagreb, Croatia.
Maja
M
Osmak
Laboratory for Cell Biology and Signalling, Division of Molecular Biology, Ruđer Bošković Institute, Bijenička 54, 10000 Zagreb, Croatia.
Andreja
A
Ambriović-Ristov
D000970:Antineoplastic Agents / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D002945:Cisplatin / Q000494:pharmacology; D000069439:Dasatinib / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D004357:Drug Synergism; D005472:Fluorouracil / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D016391:Genes, src; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D039641:Integrin beta Chains / Q000502:physiology; D016685:Mitomycin / Q000494:pharmacology; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D017354:Point Mutation; D055503:Protein Multimerization; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000235:genetics / Q000502:physiology*; D034622:RNA Interference; D014062:Tongue Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000099200:Scaffold Protein ILK
D000970:Antineoplastic Agents; D002945:Cisplatin; D000069439:Dasatinib; D004317:Doxorubicin; D005472:Fluorouracil; D039302:Integrin alphaVbeta3; D039641:Integrin beta Chains; D016685:Mitomycin; D009363:Neoplasm Proteins; D017346:Protein Serine-Threonine Kinases; D016392:Proto-Oncogene Proteins pp60(c-src); D000099200:Scaffold Protein ILK; C000599263:ITGB5 protein, human
Cisplatin; Drug resistance; HNSCC cells; Integrin αvβ3; Src; Src inhibitors