Caffeic acid suppresses cyclin D1 expression by directly binding to ribosomal protein S5 in colorectal cancer cells

Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide, and dietary components such as coffee have been epidemiologically associated with a reduced risk of CRC. However, the molecular mechanisms underlying this effect remain elusive. In this study, we found that caffeic acid, a hydrolysate of chlorogenic acid abundant in coffee, significantly suppressed colony formation in human CRC cells. Chemical pull-down assays using nano-magnetic beads combined with mass spectrometry identified ribosomal protein S5 (RPS5) as a direct binding target of caffeic acid. Molecular dynamics simulations further supported the stability of the interaction between caffeic acid and a specific binding pocket on RPS5. Mechanistically, RNA interference-mediated knockdown of RPS5 induced G1 cell cycle arrest and downregulated cyclin D1 expression at both mRNA and protein levels, without affecting its promoter activity, suggesting a post-transcriptional regulatory mechanism of cyclin D1 by RPS5. These findings reveal a previously unrecognized RPS5-cyclin D1 axis targeted by caffeic acid and provide novel mechanistic insights into the potential chemopreventive effects of coffee against CRC. Morgan, E. et al. Global burden of colorectal cancer in 2020 and 2040: incidence and mortality estimates from GLOBOCAN. Gut 72, 338–344. https://doi.org/10.1136/gutjnl-2022-327736 (2023). Gan, Y. et al. Association of coffee consumption with risk of ... [10430 chars]