Preclinical evaluation of destruxin B as a novel Wnt signaling target suppressing proliferation and metastasis of colorectal cancer using non-invasive bioluminescence imaging

Chi-Tai Yeh, Yerra Koteswara Rao, Min Ye, Wen Shi Wu, Tung Chen Chang, Liang Shun Wang, Chih Hsiung Wu, Alexander T H Wu, Yew Min Tzeng

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21 Citations (Scopus)

Abstract

In continuation to our studies toward the identification of direct anti-cancer targets, here we showed that destruxin B (DB) from Metarhizium anisopliae suppressed the proliferation and induced cell cycle arrest in human colorectal cancer (CRC) HT29, SW480 and HCT116 cells. Additionally, DB induced apoptosis in HT29 cells by decreased expression level of anti-apoptotic proteins Bcl-2 and Bcl-xL while increased pro-apoptotic Bax. On the other hand, DB attenuated Wnt-signaling by downregulation of β-catenin, Tcf4 and β-catenin/Tcf4 transcriptional activity, concomitantly with decreased expression of β-catenin target genes cyclin D1, c-myc and survivin. Furthermore, DB affected the migratory and invasive ability of HT29 cells through suppressed MMPs-2 and -9 enzymatic activities. We also found that DB targeted the MAPK and/or PI3K/Akt pathway by reduced expression of Akt, IKK-α, JNK, NF-κB, c-Jun and c-Fos while increased that of IκBα. Finally, we demonstrated that DB inhibited tumorigenesis in HT29 xenograft mice using non-invasive bioluminescence technique. Consistently, tumor samples from DB-treated mice demonstrated suppressed expression of β-catenin, cyclin D1, survivin, and endothelial marker CD31 while increased caspase-3 expression. Collectively, our data supports DB as an inhibitor of Wnt/β-catenin/Tcf signaling pathway that may be beneficial in the CRC management.

Original languageEnglish
Pages (from-to)31-41
Number of pages11
JournalToxicology and Applied Pharmacology
Volume261
Issue number1
DOIs
Publication statusPublished - May 15 2012

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Keywords

  • Apoptosis
  • Destruxin B
  • Human colorectal carcinoma
  • In vivo bioluminescence
  • Migration and invasion
  • Wnt-signaling pathway

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

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