Physapubenolide (PB), a withanolide-type compound extracted from the traditional herb Physalis minima L., has been demonstrated to exert remarkable cytotoxicity against
cancer cells; however, its molecular mechanisms are still unclear. In this study, we demonstrated that PB inhibited cell proliferation and migration in
melanoma cells by inducing cell apoptosis. The anticancer activity of PB was further verified in a
melanoma xenograft model. To explore the mechanism underlying the anticancer effects of PB, we carried out an in silico target prediction study, which combined three approaches (chemical similarity searching, quantitative structure-activity relationship (QSAR), and molecular docking) to identify the targets of PB, and found that PB likely targets 3-hydroxy-methylglutaryl
CoA reductase (HMGCR), the rate-limiting
enzyme of the
mevalonate pathway, which promotes
cancer cell proliferation, migration, and
metastasis. We further demonstrated that PB interacted with HMGCR, decreased its
protein expression and inhibited the HMGCR/YAP pathway in
melanoma cells. In addition, we found that PB could restore
vemurafenib sensitivity in
vemurafenib-resistant A-375 cells, which was correlated with the downregulation of HMGCR. In conclusion, we demonstrate that PB elicits anticancer action and enhances sensitivity to
vemurafenib by targeting HMGCR.