AT-101 induces G1/G0 phase arrest via the -catenin/cyclin D1 signaling pathway in human esophageal cancer cells

AT-101, an orally available and well-tolerated natural pan-Bcl-2 family protein inhibitor, has been reported to be effective against a variety of cancers. However, the mechanisms whereby AT-101 exhibits anticancer activity have not been fully elucidated. In this study, we demonstrated that AT-101 reduced the cell viability of human esophageal cancer cells by inducing G(1)/G(0) phase arrest and apoptosis. Apoptotic cell death occurred later than cell cycle arrest, as evidenced by an increase in the proportion of Annexin V-positive cells and cleaved caspase-3, -9 and PARP protein levels. AT-101 markedly downregulated the protein levels of phospho-retinoblastoma (Ser 780) and cyclin D1, whereas it elevated protein levels of p53 and p21(Waf1/Cip1), contributing to the inhibition of cell cycle progression. Moreover, AT-101 substantially reduced -catenin expression. XAV-939, a small molecule that inhibits the Wnt/-catenin signaling pathway by facilitating -catenin degradation, lowered -catenin and cyclin D1 protein expression to an extent similar to AT-101. XAV-939 alone resulted in G(1)/G(0) phase arrest and further induced cell cycle arrest in combination with AT-101, suggesting that the -catenin/cyclin D1 signaling pathway mediated, at least in part, the cell cycle arrest induced by AT-101. The present study may shed new light on the anticancer activity of AT-101 in relation to cell cycle arrest as well as apoptosis in human esophageal cancer cells.