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

摘要

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 gemcitabine- and 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 chemoresistance 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.