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.