Mechanistic elucidation of apoptosis and cell cycle arrest induced by 5-hydroxymethylfurfural, the important role of ROS-mediated signaling pathways

- We first report the mechanisms of 5-HMF as a biologically active ingredient.
- We first elucidate the mechanisms accounting for the anticancer action of 5-HMF.
- ROS-mediated signaling pathways conduce to A375 apoptosis and G0/G1 arrest by 5-HMF.

5-Hydroxymethylfurfural (5-HMF) has been found widely in foods through degradation of hexoses and the Maillard reaction during heat treatment of foods containing reducing sugars and amino acids in an acid environment. We have previously demonstrated 5-HMF as an antioxidant and antiproliferative ingredient. However, the action mechanisms and the underlying signaling pathways remain elusive. Therefore, in this study, experiments were carried out to elucidate the molecular mechanisms accounting for the anticancer action of 5-HMF by using MTT assay, flow cytometric and Western blot analysis. The results showed that 5-HMF exhibited a dose-dependent inhibitory effect on A375 cells, which was caused by apoptosis and G0/G1 phase arrest. Meanwhile, exposure of phosphatidylserine was observed further to prove the cell apoptosis. Further investigation on the molecular mechanisms revealed that ROS acts as an upstream mediator in 5-HMF-induced A375 cell growth inhibition. Low levels of ROS can induce DNA damage-mediated expression of P53 and phosphorylates, mitochondrial dysfunction, G0/G1 arrest and the activation of AKT and MAPKs pathways, thereby contributing to apoptosis and G0/G1 phase arrest induced by 5-HMF. Our findings imply that 5-HMF may be a candidate chemopreventive and chemotherapeutic agent because the function that induces apoptosis and/or cell cycle arrest by many anticancer drugs in susceptible cells is also exhibited by 5-HMF.

ROS acts as an upstream mediator in 5-hydroxymethylfurfural (5-HMF)-induced A375 cell growth inhibition. Low levels of ROS can induce DNA damage-mediated expression of P53 and phosphorylates, mitochondrial dysfunction, G0/G1 arrest and the activation of AKT and MAPK pathways, thereby contributing to apoptosis and G0/G1 phase arrest induced by 5-HMF.