Targeting Dishevelled, a mediator of Wnt/β-Catenin Signaling Pathway, in Human Non—Small-Cell Lung Cancer

Abstract

Lung cancer is the leading cause among cancer-related deaths worldwide. The Wnt/β-catenin signaling pathway has been proven to be activated in non—small-cell lung cancer (NSCLC). We have previously reported that Dishevelled-3 (Dvl-3), interacting with the intracellular domain of Wnt signal receptor Frizzled (Fz) and functioning as a key mediator of the Wnt/β-catenin pathway, is over-expressed in NSCLC tissue samples. We also found that knocking down Dvl-3 by siRNA suppressed NSCLC cell growth through downregulating cytosolic β-catenin level and TCF-dependent transcriptional activity, hallmarks of activation of the Wnt/β-catenin signaling pathway. Moreover, knocking down Dvl-3 induced cell-cycle arrest and sensitized NSCLC cells to cisplatin treatment. More recently, we rationally designed a small-molecule inhibitor that interrupted the interaction between the intracellular domain of Fz receptor and the PDZ domain of Dvl. We found that this compound downregulated the Wnt/β-catenin signaling pathway induced apoptosis in NSCLC cells in vitro and suppressed tumor growth in vivo. Taken together, these data suggest that small-molecular inhibition of the oncogenic Dvl function might have potential therapeutic implications in the treatment of patients with NSCLC.