Withaferin-A inhibits colorectal cancer growth and metastasis by targeting the HSP90/HIF-1α/EMT axis.

Abstract

Introduction: Withaferin-A (WA) derived from natural products can inhibit the growth and metastasis of colorectal cancer (CRC) in vitro and in vivo.

Material and methods: WA effects on colorectal cancer cells were studied using HCT116 and SW480 lines. In vitro we used shRNA knockdown, plasmid overexpression, viability, proliferation, colony, migration, and invasion assays. And Xenograft and metastasis mouse models evaluated tumor growth and toxicity. Molecular analysis used qRT-PCR, Western blot, IHC, immunoprecipitation, and RNA sequencing.

Results: Transcriptome analysis showed WA suppressed EMT, HSP90, and HIF-1α in CRC. WA inhibited HSP90, HIF-1α, E-cadherin, and their interaction. HIF-1α knockdown reduced CRC migration, invasion, and lung metastasis. 17-AAG similarly inhibited HSP90/HIF-1α and metastasis. HSP90 overexpression rescued HIF-1α expression, binding, and migratory ability in HIF-1α knockdown cells.

Conclusions: These findings indicate that WA inhibits CRC's growth, migration, and invasion by inhibiting the HSP90/HIF-1α/EMT axis. And showed that WA could be a potential therapeutic agent for CRC.