WIF-1 up-regulates expression of E-cadherin and down-regulates activities and expression MMP-2 and 9, leading to inhibition of in vitro invasiveness and tumor growth of androgen-independent PC-3 cells.

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Activation of the Wnt/β catenin pathway has been observed in a subset of prostate cancer and this pathway can modulate androgen action in the prostate, suggesting that alterations in Wnt signaling can influence prostate tumor biology. Wnt inhibitory factor-1 (WIF-1), a secreted Wnt antagonist, can bind to Wnts in the extracellular space and inhibit Wnt signaling. Down-regulation of WIF-1 expression has recently been reported in several human cancers including prostate cancer. In this study, expression of WIF-1 by stable transfection in androgen-independent PC-3 cells results in a change in morphology with more cell-cell contact formation, suggesting a less invasive tumor phenotype. This morphology is accompanied by a remarkable induction of E-cadherin expression. In addition, WIF-1 expression significantly inhibits the invasive capacity of PC-3 cells through a Matrigel-coated membrane. Zymography shows that expression of WIF-1 in PC-3 cells decreases both MMP-2 and MMP-9 activities. The decrease in MMP activities is associated with down-regulation of MMP-2 and -9 protein expression. PC-3 cells have constitutively activated AKT due to lack of PTEN. In consistence with other report, our study showed that expression of WIF-1 decreased AKT phosphorylation. Given the roles of MMPs and E-cadherin in tumorigenesis, we inoculated 2x10⁶ PC-3 cells expressing WIF-1 or parental PC-3 cells each into the right flank of nude mice. The site for the flank tumors composed of PC-3 cells expressing WIF-1 in a xenograft mouse model demonstrated residual scar with no active cancer cells. Together, our results suggest a novel therapeutic approach using a secreted Wnt antagonist for, at least, a subset of prostate cancer.