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

Abstract

BACKGROUND:

Activation of β-catenin/T-cell factor (Tcf) signaling plays a role in human carcinogenesis. This suggests a possibility that the β-catenin/Tcf signaling activated by the accumulation of β-catenin in the nucleus is related to some type of human carcinogenesis. Therefore, if β-catenin's transcriptional activity can be markedly down-regulated, tumor growth will be suppressed in β-catenin activated types of cancer.

METHODS:

To investigate the activation or suppression of β-catenin/Tcf transcription, we established a transiently transfected cell line with a constitutively active β-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 β-catenin/Tcf signaling in β-catenin activated cells. Streptonigrin inhibited the transcriptional activity of β-catenin/Tcf in SW480 cells and HEK293 cells transiently transfected with a constitutively active mutant β-catenin gene. The growth inhibitory effect of streptonigrin was more evident in β-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 β-catenin/Tcf signaling, and their inhibitory mechanism is related to the proliferation inhibitory effect on β-catenin-activated cancer cells.

GENERAL SIGNIFICANCE:

This report reveals a molecular mechanism underlying the anti-tumor effect of streptonigrin from the perspective β-catenin/Tcf signaling. Given its function in inhibiting β-catenin/Tcf signaling, streptonigrin may be of interest as a leading compound for chemotherapeutic agent against β-catenin-activated tumorigenesis.

• Authors: Seyeon Park, Sohyun Chun
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1810 Issue 12 Pg. 1340-5 (Dec 2011) ISSN: 0006-3002 [Print] Netherlands
• PMID: 21763403 (Publication Type: Journal Article)
• Copyright: 2011 Elsevier B.V. All rights reserved.

Chemical References

• DNA Primers
• TCF Transcription Factors
• beta Catenin
• Streptonigrin

Topics

• Base Sequence
• Blotting, Western
• Cell Line
• Cell Proliferation (drug effects)
• DNA Primers
• Electrophoretic Mobility Shift Assay
• Humans
• Real-Time Polymerase Chain Reaction
• Signal Transduction (drug effects)
• Streptonigrin (pharmacology)
• TCF Transcription Factors (metabolism)
• beta Catenin (metabolism)