Casein kinase 1α-dependent inhibition of Wnt/β-catenin selectively targets nasopharyngeal carcinoma and increases chemosensitivity.

Abstract

Pyrvinium tosylate (PT) is an anthelminthic drug that has recently been shown to suppress various human cancers. However, whether PT is effective in nasopharyngeal carcinoma (NPC) has not been determined to date. In this work, we show the selective efficacy of PT in NPC while sparing normal nasopharyngeal epithelial cells, and its ability to increase chemosensitivity. We show that PT at 100 and 500 nmol/l significantly inhibits growth and induces apoptosis in several NPC cell lines without affecting normal nasopharyngeal epithelial cells. Using cell culture and xenograft mouse models, PT markedly enhances cisplatin's efficacy in NPC and the combination leads to almost complete tumor inhibition. Mechanism studies show that PT suppresses active, nuclear β-catenin level and activity and increases Axin level in NPC cells. β-Catenin overexpression completely reverses the inhibitory effects of PT, confirming that β-catenin is the molecular mechanism of PT's action in NPC. In addition, the effects of PT on β-catenin and Axin levels and on Wnt signaling in NPC cells are mediated by its activation of casine kinase 1α. Our work is the first to suggest that Wnt/β-catenin is a selective target for NPC treatment, and provides the preclinical evidence on the translational potential of PT as a useful addition to the treatment armamentarium for NPC.