Protopanaxadiol (
PPD), a ginseng metabolite generated by the gut bacteria, was shown to induce
colorectal cancer cell death and enhance the anticancer effect of chemotherapeutic agent
5-FU. However, the mechanism by which
PPD promotes
cancer cell death is not clear. In this manuscript, we showed that
PPD activated p53 and endoplasmic reticulum (ER) stress and induced expression of BH3-only
proteins Puma and Noxa to promote cell death. Induction of Puma by
PPD was p53-dependent, whereas induction of Noxa was p53-independent. On the other hand,
PPD also induced prosurvival mechanisms including autophagy and expression of Bcl2 family apoptosis regulator Mcl-1. Inhibition of autophagy or knockdown of Mcl-1 significantly enhanced
PPD-induced cell death. Interestingly,
PPD inhibited expression of genes involved in
fatty acid and
cholesterol biosynthesis and induced synergistic
cancer cell death with
fatty acid synthase inhibitor
cerulenin. As
PPD-induced ER stress was not significantly affected by inhibition of new
protein synthesis, we suggest
PPD may induce ER stress directly through causing
lipid disequilibrium.