期刊
BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
卷 1810, 期 12, 页码 1340-1345出版社
ELSEVIER
DOI: 10.1016/j.bbagen.2011.06.023
关键词
beta-catenin/Tcf signaling; Inhibitor; Streptonigrin
Background: Activation of beta-cateninj-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. (C) 2011 Elsevier B.V. All rights reserved.
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