Pyrvinium Sensitizes Clear Cell Renal Cell Carcinoma Response to Chemotherapy Via Casein Kinase 1α-Dependent Inhibition of Wnt/β-Catenin.

BACKGROUND: Aberrant Wnt/β-catenin activation has been shown to play essential roles in cancer, including renal cell carcinoma (RCC). In this work, we demonstrate that Wnt/β-catenin inhibition by a Food and Drug Administration-approved drug, pyrvinium, effectively targets clear cell RCC and enhances chemotherapy agent's efficacy.
MATERIALS AND METHODS: We performed in vitro cell culture assays and in vivo xenograft tumor model to evaluate the effects of pyrvinium alone and its combination with paclitaxel, and analyzed the underlying mechanism(s) of pyrvinium's action in RCC.
RESULTS: We show that pyrvinium inhibits growth and induces apoptosis via caspase pathway in a panel of RCC cell lines. It decreases β-catenin activity and its downstream Wnt-targeted genes transcription via axin-mediated β-catenin protein reduction. Overexpression of β-catenin completely reverses the effects of pyrvinium, demonstrating that β-catenin inhibition is required for pyrvinium's action in clear cell RCC. Furthermore, we found that pyrvinium failed to decrease β-catenin protein level and activity in casein kinase 1α (CK1α)-depleted clear cell RCC cells, demonstrating that pyrvinium inhibits β-catenin in a CK1α-dependent manner. Notably, decreased tumor growth and β-catenin levels were observed in clear cell RCC xenograft mouse model treated with pyrvinium. Combination of pyrvinium and paclitaxel resulted in greater efficacy in in vitro and in vivo.
CONCLUSIONS: Our findings suggest that pyrvinium is a useful addition to the treatment armamentarium for clear cell RCC. Our work also demonstrate that targeting Wnt/β-catenin is a potential therapeutic strategy in clear cell RCC.