Colorectal cancer (CRC) is the fourth leading cause of cancer mortality worldwide. Aberrant activation of WNT/β-catenin signaling present in the vast majority of CRC cases is indispensable for CRC initiation and progression, and thus is a promising target for CRC therapeutics. Hispolon is a fungal-derived polyphenol with a pronounced anticancer effect. Several hispolon derivatives, including dehydroxyhispolon methyl ether (DHME), have been chemically synthesized for developing lead molecules with stronger anticancer activity. Herein, a DHME-elicited anti-CRC effect with the underlying mechanism is reported for the first time. Specifically, DHME was found to be more cytotoxic than hispolon against a panel of human CRC cell lines, while exerting limited toxicity to normal human colon cell line CCD 841 CoN. Additionally, the cytotoxic effect of DHME appeared to rely on inducing apoptosis. This notion was evidenced by DHME-elicited upregulation of poly (ADP-ribose) polymerase (PARP) cleavage and a cell population positively stained by annexin V, alongside the downregulation of antiapoptotic B-cell lymphoma 2 (BCL-2), whereas the blockade of apoptosis by the pan-caspase inhibitor z-VAD-fmk attenuated DHME-induced cytotoxicity. Further mechanistic inquiry revealed the inhibitory action of DHME on β-catenin-mediated, T-cell factor (TCF)-dependent transcription activity, suggesting that DHME thwarted the aberrantly active WNT/β-catenin signaling in CRC cells. Notably, ectopic expression of a dominant-active β-catenin mutant (∆N90-β-catenin) abolished DHME-induced apoptosis while also restoring BCL-2 expression. Collectively, we identified DHME as a selective proapoptotic agent against CRC cells, exerting more potent cytotoxicity than hispolon, and provoking CRC cell apoptosis via suppression of the WNT/β-catenin signaling axis.

Department of Biochemistry and Molecular Cell Biology Taipei Medical University Taipei 11031 Taiwan

Department of Biotechnology Asia University Taichung 41354 Taiwan

Department of Life Sciences The iEGG and Animal Biotechnology Research Center Rong Hsing Research Center for Translational Medicine National Chung Hsing University Taichung 40227 Taiwan

Department of Medical Research China Medical University Hospital Taichung 40447 Taiwan

Department of Organic Chemistry Andhra University Visakhapatnam 530 003 India

Department of Pediatrics Department of Medical Research Tungs' Taichung Metroharbor Hospital Wuchi Taichung 43503 Taiwan

Department of Rehabilitation Jen Teh Junior College of Medicine Nursing and Management Miaoli 35664 Taiwan

Institute of Biomedical Sciences National Chung Hsing University Taichung 40227 Taiwan

Ph D Program in Tissue Engineering and Regenerative Medicine National Chung Hsing University Taichung 40227 Taiwan

Ph D Program in Translational Medicine National Chung Hsing University Taichung 40227 Taiwan

Traditional Herbal Medicine Research Center Taipei Medical University Hospital Taipei 11031 Taiwan

University of Chemistry and Technology 166 28 Prague Czech Republic

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