Aqueous extract of Sanguisorba officinalis blocks the Wnt/β-catenin signaling pathway in colorectal cancer cells.

Meng-Ping Liu,Cong Dai,Zheng Li,Jie-Feng Chen,Wei Zhang,Christopher Wai Kei Lam,Mei-Cun Yao,Zuan-Guang Chen,Wa Li

doi:10.1039/c8ra00438b

Meng-Ping Liu, Cong Dai + Show 7 more

Open Access

https://doi.org/10.1039/c8ra00438b

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Abstract

Sanguisorba officinalis (the Chinese name is DiYu, DY) exerts significant anti-proliferative activities against colorectal cancer (CRC) cells. Since most of CRC result from the aberrant activation of the Wnt/β-catenin signaling pathway, inhibitors of the Wnt pathway are considered as promising anti-CRC agents. This study aimed to investigate whether DY could be a potential herbal Wnt inhibitor, and the bioactive constituents and underlying molecular mechanisms for DY's inhibiting activities would be studied as well. Accordingly, the inhibitory activities of DY and its main components against the Wnt pathway were assessed using the single-luciferase reporter assay based on HEK293 cells. Additionally, the levels of key Wnt-related genes or proteins were measured to verify the inhibitory effects on the Wnt pathway of CRC cells. Finally, the underlying mechanisms accounting for the efficacy of candidate drugs were explored by the transcriptomic study. Results show that DY and its tannins (RZ), and saponins (ZG) significantly inhibited the Wnt pathway of HEK293 cells activated by wnt3a. However, their respective constituents were not effective as expected. Additionally, DY and RZ prominently down-regulated the levels of β-catenin and Wnt-targeted genes including Axin2, c-Myc or CyclinD1 of three CRC cells. Transcriptomic profiling study suggests that the down-regulation of the mRNA levels of Wnt-related genes such as LPAR6 may be associated with the inhibitory effects of DY and RZ on the Wnt pathway of HT29 cells. Therefore, our studies first uncovered the blocking activity of DY on the Wnt pathway, providing evidence for the rationale of developing Wnt inhibitors from DY as anti-CRC agents.

Highlights

As the third most common carcinoma worldwide, colorectal cancer (CRC) seriously threatens human health.[1]The pathogenesis of CRC is complex and is still not clearly understood
The results show that all the DY water extracts blocked the activities of Wnt/b-catenin signaling in HEK293 cells (Fig. 1A)
Considering the integrality of the DY extract, we evaluated the effects of 15 mg mlÀ1 DY and its representative chemicals on Wnt pathway. 15 mg mlÀ1 was chosen was due to the inhibitory effects of DY was strong enough and most of the components inside were detectable at this concentration

Summary

Introduction

As the third most common carcinoma worldwide, colorectal cancer (CRC) seriously threatens human health.[1]The pathogenesis of CRC is complex and is still not clearly understood. Based on current reports, the aberrant activation of the Wnt/b-catenin pathway is believed to be a major factor contributing to the progress of CRC.[2] In this signaling, b-catenin is a key functional protein that's stabilized by a destruction complex. Namely APC, Axin, CK1 and GSK3b, are the main components of this complex, which cooperate with each other to avoid activating the Wnt pathway by degrading the cytoplasmic b-catenin.[3] Mutation of the tumour-suppressor genes or oncogenes such as APC, Axin[2], SMAD4 or KRAS would cause degradation of the complex and allows b-catenin accumulated in the cytoplasm to transfer into the cell nucleus. Some of them exhibit signi cant inhibitory effects (IC50 LGK947 1⁄4 0.4 nM),[7,8] their cytotoxicity remains a critical issue to be concerned.[9]

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