Blocking integrin [beta]1 decreases adhesion in chemoresistant urothelial cancer cell lines

Treatment failure in metastatic bladder cancer is commonly caused by acquisition of resistance to chemotherapy in association with tumor progression. Since alterations of integrins can influence the adhesive and invasive behaviors of urothelial bladder cancer cell lines, the present study aimed to evaluate the role of integrins in bladder cancer cells with acquired resistance to standard first-line chemotherapy with gemcitabine, and cisplatin. Therefore, four gemcitabineand four cisplatin-resistant sublines out of a panel of four parental urothelial bladder cancer cell lines (TCC-SUP, HT1376, T24, and 5637) were used. Expression of integrin subunits [alpha]3, [alpha]5, [alpha]6, [beta]1, [beta]3, and [beta]4 was detected using flow cytometry. Adhesion and chemotaxis were analyzed. For functional assays, integrin [beta]1 was attenuated with a blocking antibody. In untreated cells, chemotaxis was upregulated in 3/4 gemcitabine-resistant sublines. In cisplatin-resistant cells, chemotaxis was enhanced in 2/4 cell lines. Acquired chemo-resistance induced the upregulation of integrin [beta]1 in all four tested gemcitabine-resistant sublines, as well as an upregulation in 3/4 cisplatin-resistant sublines compared with parental cell lines. Following the inhibition of integrin [beta]1, adhesion to extracellular matrix components was downregulated in 3/4 gemcitabine-resistant sublines and in all four tested cisplatin-resistant sublines. Since integrin [beta]1 is frequently upregulated in chemoresistant urothelial cancer cell lines and inhibition of integrin [beta]1 may influence adhesion, further studies are warranted to evaluate integrin [beta]1 as a potential therapeutic target for bladder cancer in vivo.