HSC-5

Novel Small Molecules KY19382 and KY19334 Inhibit the Migration, Invasion, Proliferation and Transformation of Human cSCC Cells

The Wnt/β-catenin pathway is an attractive target for drug development in various diseases; however, efforts to target it have been limited due to its concerning role in cancer. We previously developed KY19382 and KY19334, small molecules that inhibit the cytosolic function of CXXC-type zinc finger protein 5 (CXXC5), as safe therapeutic agents to restore the suppressed Wnt/β-catenin signaling in several intractable diseases, but the effects of these small molecules on cancer have not been determined.

To investigate any effect of these compounds on cancer progression, we treated human cSCC cells with KY19382 or KY19334. HaCaT cell line was used as a control for normal keratinocytes. Intriguingly, KY19382 or KY19334 inhibited the proliferation of the two human cSCC cell lines (Fig. 1a). Boyden chamber assay using human cSCC cell lines and a normal keratinocyte cell line also revealed that these two compounds significantly inhibited migration and invasion of the two human cSCC cell lines (Fig. 1b, c). Likewise, KY19382 and KY19334 markedly inhibited the transformation of both HSC-1 and HSC-5 cells (Fig. 1d).

To better understand the inhibitory effects of these compounds on cancer progression, we next monitored the expression levels of cytosolic CXXC5 and CDK1, potential targets of these compounds, and their associated markers in human cSCC cell lines. Differently from normal HaCaT cells, the expression level of CXXC5, especially within the cytoplasm, was very low in both HSC-1 and HSC-5 cells, supporting that cytosolic CXXC5 is not a functional target of the compounds in cSCC cells. The expression of CDK1 was significantly increased in both HSC-1 and HSC-5 cells (Fig. 1e). KY19382 and KY19334 effectively downregulated CDK1 expression, particularly in two human cSCC cell lines (Fig. 1f). Overall, KY19382 and KY19334 inhibit cellular transformation of human cSCC cells, but not normal cells, with suppression of CDK1 expression.