FH535 Inhibits Proliferation and Motility of Colon Cancer Cells by Targeting Wnt/β-catenin Signaling Pathway

Abstract

Aberrant Wnt/β-catenin pathway activation is frequently observed in human colorectal cancer (CRC) and has become a promising target for CRC treatment. Our study aimed to evaluate the effect of FH535, a small molecule inhibitor of Wnt/β-catenin pathway, on two colon cancer cell lines, HT29 and SW480. We found FH535 significantly inhibited colon cancer cell proliferation in vitro and induced cell cycle arrest. Moreover, FH535 inhibited colon cancer xenograft growth in vivo. Wound-healing assay and Transwell assay revealed that FH535 notably suppressed migration and invasion of SW480 cells. FH535 also repressed expression of cancer stem cell markers, CD24, CD44 and CD133 in HT29 cells. Real time-quantitative PCR and Western blotting revealed that targeting Wnt/β-catenin pathway using FH535 effectively downregulated target genes including cyclin D1 and survivin at mRNA and protein level, which contributed to the FH535-induced inhibitory effect on colon cancer cell proliferation. As mechanisms for suppressing cancer cell motility, FH535 downregulated expression of matrix metalloproteinase-7 and -9, Snail and vimentin. RNA sequencing revealed that FH535 prominently altered multiple biological pathways associated with DNA replication, cell cycle and metabolism. Our study highlights the anti-cancer effect of FH535 on colon cancer and presents its potential in colon cancer treatment.

Improving anticancer activity towards colon cancer cells with a new p53‐activating agent

“…A possible explanation for the enhanced sensitization of colon cancer cells to the effects of known chemotherapeutic agents, by SYNAP may be related to the ability of SYNAP to reduce the levels of survivin, a key protein in carcinogenesis almost uniformly overexpressed in these tumours (Hernandez et al, ). In fact, survivin overexpression has been associated with cancer progression, chemoresistance and angiogenesis, with apoptosis inhibition and shortened survival in cancer patients (Ling et al, ; Hernandez et al, ; Souza et al, ; Singh et al, ; Chen et al, ). In addition, inhibition of survivin improved the uptake of drugs by cancer cells with a notable enhancement of their anticancer activity (Singh et al, ).…”

Suppression of the SDF‑1/CXCR4/β‑catenin axis contributes to bladder cancer cell growth inhibition in�vitro and in�vivo

“…FH535 is an inhibitor of Wnt/β-catenin signaling and dual antagonist of PPARγ/δ activity. It suppresses β-catenin/Tcf-mediated transcription and inhibits β-catenin and GRIP1 recruitment to PPARγ and δ (26,27).…”

Taxifolin, a natural flavonoid interacts with cell cycle regulators causes cell cycle arrest and causes tumor regression by activating Wnt/ β -catenin signaling pathway

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