A grape-derived ally: how resveratrol disarms lipid-driven resistance to anticancer agents in colorectal cancer

Abstract

Resveratrol (RSV), a stilbene polyphenol naturally concentrated in the grapevine and present in red wine, has long been recognized for its bioactive potential. Beyond its well known antioxidant properties, increasing evidence supports its relevance in oncology, particularly in colorectal cancer (CRC), where metabolic rewiring contributes to therapeutic resistance. Among these adaptations, cancer cells frequently amplify lipid metabolism, especially phosphatidylcholine (PC) synthesis through the Kennedy pathway and the Lands cycle, with LPCAT2 emerging as a pivotal enzyme linking membrane remodeling, lipid droplet (LD) accumulation, and chemoresistance. In this context, we investigated the capacity of RSV to interfere with PC metabolism and restore therapeutic sensitivity. In chemoresistant CRC models overexpressing LPCAT2 (HT29 and SW620 LPCAT2), RSV induced apoptosis and significantly impaired cell survival. Mechanistically, RSV decreased key Kennedy pathway enzymes while leaving LPCAT2 levels and LD abundance unchanged, suggesting that its pro apoptotic activity arises from a selective disruption of PC remodeling. Drug combination assays further revealed that RSV acts as a potent chemosensitizer. When combined with anticancer agents (5 fluorouracil, oxaliplatin and the combination of the two) in CRC management, RSV produced robust synergistic effects. These interactions translated into increased cytotoxicity at lower drug doses, highlighting a clinically relevant strategy to mitigate toxicity while maintaining efficacy. Altogether, our findings position RSV, a signature molecule of grapevine and wine, as a promising metabolic adjuvant capable of targeting vulnerabilities in PC biosynthesis and enhancing the therapeutic response to chemotherapeutic drug. This work underscores the translational potential of wine derived polyphenols as modulators of cancer cell metabolism and as valuable allies in overcoming chemoresistance in CRC.

References

Cotte, A.; Aires V.; Fredon M.; Limagne E.; DerangèreV.; Thibaudin M.; Humblin E.; Scagliarini A.; Pais de Barros J.P.; Hillon P.; Ghiringhelli F.; Delmas D. (2018) Lysophosphatidylcholine acyltransferase 2-mediated lipid droplet production supports colorectal cancer chemoresistance. Nature Communications, 9(1): 322.