Dehydroxyhispolon Methyl Ether, A Hispolon Derivative, Inhibits WNT/β-Catenin Signaling to Elicit Human Colorectal Carcinoma Cell Apoptosis

Abstract

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.

Wnt signaling in colorectal cancer: pathogenic role and therapeutic target

“… Abbreviated name Full official name Classification Intervention mechanism References 1 ACBP Anticancer bioactive peptide Novel bioactive peptide ACBP can inhibit phospho-LRP6 and stimulate phospho-β-catenin. [ 168 ] 2 ND MiR-377-3p MicroRNA Directly target ZEB2 and XIAP to inhibit Wnt/β-catenin signaling [ 169 ] 3 DHME Dehydroxyhispolon methyl ether Hispolon derivatives Inhibits β-catenin-mediated T cell factor (TCF)-dependent transcriptional activity [ 170 ] 4 ND SSTC3 New small molecule CK1α activator The target CK1α inhibits the growth of mouse CRC xenografts and attenuates the growth of patient-derived metastatic CRC xenografts [ 171 ] 5 CQD Chlorquinaldol Bacteriostatic agent Inhibit the acetylation of β-catenin, destroy the interaction between β-catenin and T cell factor 4 (TCF4), and reduce the binding of β-catenin to Wnt target gene promoters, and down-regulate the expression of these target genes [ 172 ] 6 ND KY7749 Compound Inhibit the proliferation and transformation of CRC cells, independently of β-catenin degradation of Ras [ 173 ] 7 ND Niclosamide Antihelminth compound Inhibit Wnt/β-catenin pathway activation, down-regulate Dvl2, and reduce downstream β-catenin signal transduction [ 174 ] 8 ND KHDRBS3 Genes encoding KH RNA binding domains, signal transduction related 3 KHDRBS3 may play a key role in acquiring stem cell characteristics (such as drug resistance and spheroid/organoid formation) by regulating the expression of CD44 variants and the Wnt signaling pathway [ 175 ] 9 ND KYA1797K ...…”

Antibladder Cancer Effects of Excavatolide C by Inducing Oxidative Stress, Apoptosis, and DNA Damage In Vitro

“…Annexin V/7AAD reagents (Strong Biotech Inc., Taipei, Taiwan), containing Annexin V-FITC and 7AAD at the final condition (1:1000 and 1 μg/mL), were incubated with cells for 30 min to detect apoptosis [ 33 , 44 ] according to the user’s manual. Finally, cells were analyzed by flow cytometry.…”

Biological Activities of Hispolon

“…In this combinational approach, hispolon and doxorubicin improved apoptosis than in distinct treatment. Among various derivates of hispolon, dehydroxyhispolon methyl ether (DHME) exhibited strong anticancer activity in a group of colorectal cancer cell lines 39 . DHME was more effective than hispolon and a selective proapoptic agent through the downregulation of WNT/β-catenin signaling pathway.…”