Weichang'an suppressed migration and invasion of HCT116 cells by inhibiting Wnt/β‐catenin pathway while upregulating ARHGAP25

Abstract

Evidence suggests that Weichang'an (WCA) inhibited the metastasis of colorectal cancer (CRC) in vitro and downregulates oncogenic β‐catenin; more intriguingly, we also found an upregulation of ARHGAP25 in this process. This study aimed to investigate the mechanisms by which WCA regulated CRC metastasis in vitro. Here, HCT116 cells were transfected with siRNAs to interfere ARHGAP25 expression. WCA decoction, XAV939 (a specific Wnt/β‐catenin pathway inhibitor), and LiCl (an activator for Wnt/β‐catenin pathway) were used for treatment. Cell migratory and invasive capacities were determined using Transwell chamber. The activation of Wnt/β‐catenin pathway was assessed by determining the expression of MMP7, MMP9, ZEB1, and β‐catenin. The study suggests that WCA inhibited the migration and invasion of HCT116 cells and suppressed the activation of Wnt/β‐catenin pathway, as evidenced by retarding MMP7, MMP9, ZEB1, and β‐catenin. However, siRNA–ARHGAP25 resulted in the opposite. In siRNA–ARHGAP25‐transfected HCT116 cells, WCA (0.4 mg/mL) induced the antimetastatic effects and the inactivation of Wnt/β‐catenin pathway was remarkably reversed with additional LiCl treatment. Our study concludes that inhibiting Wnt/β‐catenin pathway while promoting ARHGAP25 was the mechanism, whereby WCA retarded migration and invasion of CRC in vitro.

A novel BRET‐Based GAP assay reveals phosphorylation‐dependent regulation of the RAC‐specific GTPase activating protein ARHGAP25

“…[14][15][16]28 Recently, the role of ARHGAP25 in tumor cell metastasis has also been recognized. [18][19][20][21][22][23] Despite its emerging immunological and oncological importance, the post-translational control of ARHGAP25 is almost entirely unknown, prompting us to explore the regulation of this protein further.…”

“…Therefore, we aimed to systematically examine the possible role of these phospho-sites in leukocytes, the cell types with the highest ARHGAP25 expression. Recently, more and more papers report the involvement of ARHGAP25 in tumor migration and metastasis, [18][19][20][21][22][23] rendering the post-translational modifications of ARHGAP25 all the more relevant.…”

Could inhibition of metalloproteinases be used to block the process of metastasis?

“…Many microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) have been related to cancer, and its aberrant expression has been detected in solid tumors and in hematological malignancies. [81][82][83] Many of miRNAs or lncRNAs genes are located in genomic regions associated with cancer or in fragile sites, which suggests an important role in the disease evolution. 84,85 In this sense, in recent years, the two types of RNAs have emerged as extremely useful in disease diagnosis.…”

Potential Role of Traditional Chinese Medicines by Wnt/β-Catenin Pathway Compared With Targeted Small Molecules in Colorectal Cancer Therapy

“…Recent studies showed that ZJW extracts can exert anti-tumorigenic effects by suppressing the canonical Wnt/β-catenin pathway in animal and cell experiments, similar to that seen with 5-HTR antagonists ( Pan et al, 2017 ). Weichang’ an (WCA) is a traditional Chinese medicinal formula used as an anticancer drug and the experimental data also showed the anti-metastatic function by blunting the activation of Wnt/β-catenin pathway and reducing the expression of MMP9 and the EMT-related protein ZEB1 ( Tao et al, 2019 ). Furthermore, TCM formulations could provide an adjunct for chemotherapy in cancer patients.…”