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Overexpression of integrin αVβ3 in tongue squamous carcinoma cells (CAL27) inhibits migration and confers resistance several antitumor drugs

Cell surface receptors for the extracellular matrix (ECM), such as the integrins, play key roles in the regulation of normal and tumor cell migration and survival. In breast cancer, melanoma and glioma, malignant progression is associated with expression of tumor cell integrin αvβ3. Conversely, in hepatocellular carcinoma and ovarian carcinoma the expression of integrin αvβ3 leads to tumor suppression. In addition, the role of integrin αvβ3 in chemotherapeutic drug resistance has been confirmed but also warrants further exploration because of conflicting data obtained in different cell models. We have recently described in human laryngeal carcinoma cell line (HEp2) a novel mechanism of resistance to cisplatin, mitomycin C and doxorubicin, mediated by αvβ3 integrin, involving glutathione (GSH) dependent increased ability of αvβ3 expressing cells to eliminate drug induced reactive oxygen species (ROS). In the present study we investigated whether similar mechanism exists in tongue squamous carcinoma (Cal27) cell model. The αvβ3-negative Cal27 cells were transfected with a plasmid expressing human β3 integrin subunit and stable transfectants were selected through monitoring expression by flow cytometry. We found that two Cal27-derived stable transfectants with increased amount of αvβ3 integrin expression are resistant to cisplatin, doxorubicin, mitomycine C and even to etoposide and camptothecin, as compared to parental Cal27 cells. The resistance was independent of GSH since Cal27 and Cal27-αvβ3 stable transfectants contain equal amount of total cell GSH and inhibition of GSH synthesis using buthionine sulfoximine did not change sensitivity to neither of abovementioned ant-cancer drugs. Cell migration toward serum of Cal27 and Cal27-derived stable transfectants was performed using Boyden chamber assay, and showed that the expression of integrin αvβ3 strikingly inhibited migration thus indicating αvβ3-mediated decreased invasion potential. Our findings confirm that αvβ3 integrin mediates resistance to several antitumor drugs in two cancer cell lines through different mechanisms. In addition, our results suggest that αvβ3 integrin actually inhibits tumor progression. Therefore αvβ3 integrin may not be an appropriate target for therapeutic inhibition but still could be used as a potential target molecule for tumor therapy.

Integrin αVβ3; drug-resistance; migration

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