Resveratrol Modulates Chemosensitisation to 5-FU via beta 1-Integrin/HIF-1 alpha Axis in CRC Tumor Microenvironment

Frequent development of resistance to chemotherapeutic agents such as 5-flourouracil (5-FU) complicates the treatment of advanced colorectal cancer (CRC). Resveratrol is able to utilize beta 1-integrin receptors, strongly expressed in CRC cells, to transmit and exert anti-carcinogenic signals, but whether it can also utilize these receptors to overcome 5-FU chemoresistance in CRC cells has not yet been investigated. Effects of beta 1-integrin knockdown on anti-cancer capabilities of resveratrol and 5-FU were investigated in HCT-116 and 5-FU-resistant HCT-116R CRC tumor microenvironment (TME) with 3D-alginate as well as monolayer cultures. Resveratrol increased CRC cell sensitivity to 5-FU by reducing TME-promoted vitality, proliferation, colony formation, invasion tendency and mesenchymal phenotype including pro-migration pseudopodia. Furthermore, resveratrol impaired CRC cells in favor of more effective utilization of 5-FU by down-regulating TME-induced inflammation (NF-kB), vascularisation (VEGF, HIF-1 alpha) and cancer stem cell production (CD44, CD133, ALDH1), while up-regulating apoptosis (caspase-3) that was previously inhibited by TME. These anti-cancer mechanisms of resveratrol were largely abolished by antisense oligonucleotides against beta 1-integrin (beta 1-ASO) in both CRC cell lines, indicating the particular importance of beta 1-integrin receptors for the 5-FU-chemosensitising effect of resveratrol. Lastly, co-immunoprecipitation tests showed that resveratrol targets and modulates the TME-associated beta 1-integrin/HIF-1 alpha signaling axis in CRC cells. Our results suggest for the first time the utility of the beta 1-integrin/HIF-1 alpha signaling axis related to chemosensitization and overcoming chemoresistance to 5-FU in CRC cells by resveratrol, underlining its potential supportive applications in CRC treatment.

Automated summary

Resveratrol can enhance the sensitivity of colorectal cancer cells to 5-FU by regulating the beta 1-integrin/HIF-1α signaling axis, leading to suppression of cancer cell growth and invasion, inhibition of inflammation and cancer stem cell production. These findings highlight the potential application of resveratrol in the treatment of colorectal cancer by overcoming chemoresistance to 5-FU.