Nigericin exerts anticancer effects on human colorectal cancer cells by inhibiting Wnt/{beta}-catenin signaling pathway

Nigericin, an antibiotic derived from Streptomyces hygroscopicus that works by acting as an H+, K+ and Pb2+ ionophore, has exhibited promising anticancer activity. The main purpose of this study is to investigate its inhibitory effects on Wnt/β-catenin signaling pathway in colorectal cancer (CRC) cells and clarify the underlying mechanism. We exposed two CRC lines (SW620 and KM12) to increasing concentrations of nigericin for different time periods and the 50% inhibiting concentration (IC50) values were evaluated. Our data showed that nigericin treatment significantly reduced tumor cell proliferation in dose- and time-dependent manners in CRC cells. The subsequent experiments in vitro and in vivo implied that nigericin could significantly suppress the tumor growth, migration and invasion, and induce the apoptosis of CRC cells. Our results of western blot and immunofluorescence assay showed that nigericin could suppress the Wnt/β-catenin signaling pathway in CRC cells with dose-dependent increased expressions of downstream effectors and target proteins. To further elucidate the inhibitory effects of nigericin via a β-catenin-dependent signaling mechanism, we established the stably β-catenin over-expression CRC cells. Western blot, SuperTOPflash luciferase reporter and immunoprecipitation assays all confirmed β-catenin as a critical intermediary and player in Wnt/β-catenin pathway, and nigericin exerted anti-cancer effects on CRC cells by directly targeting the β-catenin destruction complex. These results suggested that Wnt/β-catenin signaling might have an essential role in CRC progression. Nigericin targeting Wnt/β-catenin signaling might provide new insight into the molecular mechanism of nigericin towards cancer cells, and suggest possible clinical application in CRC.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2BSDXG6