Differential Uridyl-diphosphate-Glucuronosyl Transferase 1A enzymatic arsenal explains the specific cytotoxicity of resveratrol towards tumor colorectal cells

Resveratrol belongs to the Bioactive Food Component (BFC) family. It seems admitted that its cytotoxic action impacts tumor cells and spares healthy cells, but the published proofs remain rare. We hypothesized that cells may differentially metabolize resveratrol and lead to different systemic impacts. For this, resveratrol metabo-lization was evaluated by ultra-high-performance liquid chromatography (UHPLC) coupled with diode array detection (DAD), and correlated with the expression of Uridyl-diphosphate-Glucuronosyl Transferase 1A (UGT1A) genes. The expression of UGT1A genes in human colorectal tissues was studied with RNAseq databases. Functional validation of UGT1A enzymes implication in resveratrol sensitivity of colorectal cells established by UGT1A expression modulation. As resveratrol impacts the S phase of the cell cycle, nucleotide metabolic balance was assessed. We found that resveratrol was more cytotoxic in cells with downregulation of UGTs, i.e. tumor cells. Conversely, overexpression of the UGT1A10 gene in an initial resveratrol-sensitive tumor cell line restored the metabolization accompanied by cytotoxicity diminution. Resveratrol affected intestinal sensitive tumor cell homeostasis with a cell growth/proliferation decoupling, cell-cycle modulation, and UXP/AXP nucleotide imbalance resulting in a global reduction of transcription and translation. This impact on global cell activity was restricted to tumor cells. This study improves resveratrol's general knowledge and explains how its antitumor action can spare non-tumor cells. It also paves the way to select colorectal tumors eligible for resveratrol treatment potentiation without additional toxicity to healthy digestive tissues.

Automated summary

This study investigated the differential impact of resveratrol on tumor cells and healthy cells by evaluating its metabolism and the expression of UGT1A genes. The findings revealed that resveratrol was more cytotoxic to tumor cells with downregulated UGTs, while overexpression of UGT1A10 gene reduced its cytotoxicity. Resveratrol also affected the cell cycle, nucleotide metabolism, and global transcription and translation in intestinal sensitive tumor cells. This study enhances our understanding of the antitumor action of resveratrol and provides insights for its selective treatment in colorectal tumors.