Wnt Inhibitory Factor Inhibits Lung Cancer Cell Growth
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Objective:
Aberrant activation of the Wnt signaling pathway is associated with the pathogenesis of multiple cancers, including non-small cell lung cancer (NSCLC). Wnt inhibitory factor (WIF-1) is a secreted Wnt antagonist. Recently, we reported that the WIF-1 promoter is silenced by hypermethylation in a majority of lung cancer tumors and cell lines. Our objective was to determine if restoration of WIF-1 function could inhibit lung cancer cell growth.
Methods:
We transfected a WIF-1 plasmid into NSCLC cell lines and measured cell growth in culture. We also treated NSCLC cell lines and normal airway epithelial cells with purified recombinant WIF-1 protein. To test WIF-1 activity in vivo, we created lung cancer tumor xenografts in 16 mice, using the H460 lung cancer cell line. Then, we injected the WIF-1 plasmid vector near the tumors in 8 mice. We injected empty vector as a control in the other 8 mice.
Results:
Transfection with WIF-1 plasmid inhibited growth of NSCLC cells and decreased beta-catenin levels in the cells. The recombinant WIF-1 protein also inhibited growth of NSCLC cells, in a dose-dependent manner, but had no effect on normal airway epithelial cells. The peritumoral injections of recombinant WIF-1 significantly inhibited the tumor xenograft growth, as measured by total tumor volume after 3 weeks (p<.05).
Conclusions:
Restoration of WIF-1 function, either through plasmid transfection or through treatment with WIF-1 protein inhibits NSCLC cell growth and causes apoptosis in NSCLC cells. Peritumoral injection of the WIF-1 plasmid vector also inhibits tumor growth. These results suggest that WIF-1 may have potential as a therapy for non-small cell lung cancer and that further in vivo studies are warranted. We are currently treating mice tumor xenografts with recombinant WIF-1 protein.
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