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

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.

• Authors: 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
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 261 Issue 1 Pg. 31-41 (May 15 2012) ISSN: 1096-0333 [Electronic] United States
• PMID: 22465936 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
• Depsipeptides
• TCF4 protein, human
• Transcription Factor 4
• Transcription Factors
• beta Catenin
• destruxin B

Topics

• Animals
• Antineoplastic Agents (isolation & purification, pharmacology)
• Apoptosis (drug effects)
• Basic Helix-Loop-Helix Leucine Zipper Transcription Factors (genetics)
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Colorectal Neoplasms (drug therapy, pathology)
• Depsipeptides (isolation & purification, pharmacology)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• HCT116 Cells
• HT29 Cells
• Humans
• Luminescent Measurements
• Metarhizium (chemistry)
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Transcription Factor 4
• Transcription Factors (genetics)
• Wnt Signaling Pathway (drug effects)
• Xenograft Model Antitumor Assays
• beta Catenin (genetics)