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Over-expression of Wnt genes (e.g. Wnt 7b) and down-regulation of secreted Wnt antagonist expression (e.g. sFRP1 and WIF-1) have been reported in human urinary bladder cancer. The down-regulation of sFRP1 and WIF-1 is associated with the hypermethylation of CpG islands in their promoters, suggesting their role as tumor suppressors, an etiology for their loss of function, and possible therapeutic intervention strategies. In this study, we have established stable cell lines overexpressing WIF-1 in human invasive urinary bladder cancer T24 cell line. T24 cells with WIF-1 over-expression exhibited a significant G1 arrest in cell cycle progression and a decrease in cellular proliferation when compared to T24 cells with vector control transgenes. Consistently, p27/KIP1 protein expression is also up-regulated, and SKP-2 is down-regulated in T24 cells overexpressing WIF-1 gene. These results suggest G1 arrest and inhibition of cell growth by WIF-1 over-expression may be mediated through down-regulation of SKP-2 and a resultant accumulation of p27/KIP. In addition, we have shown that WIF-1 expression in T24 cells results in an inhibition of constitutive AKT activation and increased chemosensitivity to paclitaxol. Taken together, our findings should encourage the development of WIF-1 as a novel agent or in combination with other therapeutic drugs for the treatment of human urinary bladder cancer.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]