engleski

Integrin αvβ3 mediated drug resistance in human tongue squamous carcinoma cells

Integrin αvβ3 was found to be expressed in a variety of tumors in which it promotes tumor growth, metastasis and survival. The aim of this work is to investigate the influence of de novo expression of integrin αvβ3 in human tongue squamous carcinoma cells Cal27 on the sensitivity to antitumor drugs and migration. Transfection of Cal27 cells with a plasmid containing a gene for integrin subunit β3 led to isolation of cell clones, which differ from the Cal27 cells in de novo expression of integrin αvβ3 and increased expression of integrin αvβ5. These clones show resistance to antitumor drugs that act at the DNA level as compared to parental cells, which is a consequence of de novo expression of integrin αvβ3. Western blot analysis of the expression of kinases through which integrins can transfer signals into the cell, showed a reduced amount of tyrosin kinase Src and pSrc(Y418). Knockdown of Src expression using siRNA, as well as inhibition of Src phosphorylation Y418 using dasatinib, in Cal27 cells conferred resistance to antitumor drugs indicating that downregulation of pSrc(Y418) is responsible for observed resistance. Reduced migration ability shown in integrin β3-stably transfected cell clones is very likely due to the reduced amount of pSrc. Our results indicate that drugs that inhibit the phosphorylation of Src(Y418), identified as a target for treatment of many cancers, cannot be used simultaneously with antitumor drugs which act at the DNA level, as they may have a lower therapeutic effect in tumor cells expressing integrin αvβ3.

integrin αvβ3; integrin αvβ5; integrin mediated drug resistance; pSrc (Y418); ILK; migration

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