Abstract
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.
Highlights
Melanoma is a considerably malignant skin cancer with a low survival rate [1]
We identified the target of PB by a combinatorial target prediction strategy and demonstrated that PB interacted with hydroxy-methylglutaryl CoA reductase (HMGCR) and decreased HMGCR protein expression
PB significantly inhibits proliferation and induces apoptosis in melanoma cells We first measured the effects of PB on cell viability by CCK8 assay and found that PB inhibited cell proliferation in a dose- and time-dependent manner (Fig. 1b, c), with IC50 values (72 h) of 1.225 and 1.416 μM in A-375 and SK-MEL5 cells, respectively
Summary
Melanoma is a considerably malignant skin cancer with a low survival rate [1]. A majority of drugs approved for melanoma treatment have mitigated effectiveness owing to acquired resistance [2, 3]. The screening of bioactive compounds will become a potential effective tactic for cancer treatment, including melanoma. Withanolides, a class of steroid derivatives extracted from Physalis minima L., have attracted significant attention due to having multiple bioactivities, such as anti-inflammatory, antitumor, and antimicrobial activities [8, 9]. Physapubenolide (PB), a withanolide compound isolated from Physalis minima L, has been reported to induce apoptosis and decrease the level of glycolysis through the Akt/p53 pathway in hepatocellular carcinoma cells and trigger apoptosis and autophagy by downregulating TIGAR in breast cancer cells [10, 11]. The effects of PB on melanoma cells and the underlying molecular mechanisms remain unclear. Investigation of the anticancer molecular mechanisms induced by PB could potentially lead to the development of this compound as a novel anticancer agent
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