Targeting the Wnt/beta-catenin pathway in renal cell carcinoma

Advanced renal cancer still has a very poor prognosis. In this regard recent investigations demonstrated a constitutive activation of the Wnt signaling pathway in renal cell carcinoma (RCC) thereby promoting an exaggerated cell proliferation. Especially, β-catenin overactivation and the functional loss of endogenous Wnt antagonists are associated with RCC carcinogenesis and progression. Thus, influencing Wnt signaling might represent a promising target in RCC treatment. It was recently confirmed that ethacrynic acid (EA), ciclopirox olamine (CIC) and piroctone olamine (PO) can inhibit Wnt signaling in various cancer cell lines. Herein we investigated their cytotoxic potential towards human RCC cells and their influence on the Wnt pathway concerning apoptosis as determined by 3,3'-dihexyloxacarbocyanine iodide (DiOC6) and propidium iodide (PI) staining in flow cytometry and immunoblotting. All three agents, EA, CIC and PO triggered a significant apoptotic activity in tested RCC cell lines in a time- and concentration-dependent manner. Moreover, exposure to CIC and PO decreased the expression of β-catenin as the pivotal feature within the canonical Wnt pathway. However, β-catenin expression increased upon the treatment with EA. These results reveal a significant selective induction of apoptosis by EA, CIC and PO and suggest a suppression of RCC survival in part due to inhibition of Wnt/β-catenin signaling. The development of targeted-therapies affecting the Wnt signaling pathway might therefore lead to novel treatment options for RCC patients.