Streptonigrin inhibits beta-Catenin/Tcf signaling and shows cytotoxicity in beta-catenin-activated cells.

摘要

BACKGROUND: Activation of beta-catenin/T-cell factor (Tcf) signaling plays a role in human carcinogenesis. This suggests a possibility that the beta-catenin/Tcf signaling activated by the accumulation of beta-catenin in the nucleus is related to some type of human carcinogenesis. Therefore, if beta-catenin's transcriptional activity can be markedly down-regulated, tumor growth will be suppressed in beta-catenin activated types of cancer. METHODS: To investigate the activation or suppression of beta-catenin/Tcf transcription, we established a transiently transfected cell line with a constitutively active beta-catenin mutant gene whose product is not degraded. This cell line was also co-transfected with luciferase reporter gene constructs containing either an optimized (TOPflash) or mutant (FOPflash) Tcf-binding element. RESULTS: We identified the inhibitory effect of streptonigrin against beta-catenin/Tcf signaling in beta-catenin activated cells. Streptonigrin inhibited the transcriptional activity of beta-catenin/Tcf in SW480 cells and HEK293 cells transiently transfected with a constitutively active mutant beta-catenin gene. The growth inhibitory effect of streptonigrin was more evident in beta-catenin-activated cancer cells than in non-activated cancer cells. The electrophoresis mobility shift assay showed that the binding of Tcf complexes with their specific DNA-binding sites was suppressed by streptonigrin. Conclusion: Streptonigrin is a negative regulator of beta-catenin/Tcf signaling, and their inhibitory mechanism is related to the proliferation inhibitory effect on beta-catenin-activated cancer cells. GENERAL SIGNIFICANCE: This report reveals a molecular mechanism underlying the anti-tumor effect of streptonigrin from the perspective beta-catenin/Tcf signaling. Given its function in inhibiting beta-catenin/Tcf signaling, streptonigrin may be of interest as a leading compound for chemotherapeutic agent against beta-catenin-activated tumorigenesis.