Abstract
The deregulation of the Wnt/β-catenin signaling pathway is a central event in colorectal cancer progression, thus a promising target for drug development. Many natural compounds, such as flavonoids, have been described as Wnt/β-catenin inhibitors and consequently modulate important biological processes like inflammation, redox balance, cancer promotion and progress, as well as cancer cell death. In this context, we identified the chalcone lonchocarpin isolated from Lonchocarpus sericeus as a Wnt/β-catenin pathway inhibitor, both in vitro and in vivo. Lonchocarpin impairs β-catenin nuclear localization and also inhibits the constitutively active form of TCF4, dnTCF4-VP16. Xenopus laevis embryology assays suggest that lonchocarpin acts at the transcriptional level. Additionally, we described lonchocarpin inhibitory effects on cell migration and cell proliferation on HCT116, SW480, and DLD-1 colorectal cancer cell lines, without any detectable effects on the non-tumoral intestinal cell line IEC-6. Moreover, lonchocarpin reduces tumor proliferation on the colorectal cancer AOM/DSS mice model. Taken together, our results support lonchocarpin as a novel Wnt/β-catenin inhibitor compound that impairs colorectal cancer cell growth in vitro and in vivo.
Highlights
Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second most common cause of cancer death
It has been shown that natural compounds, including chalcones, have growth-inhibitory properties in cancer cell lines by modulating Wnt/β-catenin signaling [17,18]
We evaluated whether lonchocarpin, a chalcone isolated from Lonchocarpus sericeus, is able to inhibit the Wnt signaling pathway in human colorectal cancer cell lines RKO
Summary
Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second most common cause of cancer death. According to World Health Organization (WHO), it is expected that there were 1.8 million cases and 862,000 deaths in 2018 [1]. Sporadic CRC initiation, promotion, and progression is mostly driven by a sequence of known genetic mutations in key signaling pathways, frequently related to DNA damage response and sustained proliferation in the absence of growth factors. In CRC, 93% of the cases have at least one mutation of one Wnt/β-catenin pathway component [2]. The most frequently mutated gene in colorectal cancer is APC (adenomatous polyposis coli) that is a β-catenin destruction complex component. APC mutation occurs in 81% of non-hypermutated
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