Identification of HMGCR as the anticancer target of physapubenolide against melanoma cells by in silico target prediction

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.

Withanolides: Promising candidates for cancer therapy

“…A series of studies have demonstrated that withaferin A may have the potential for skin cancer treatment (Kalthur & Pathirissery, 2010; Li & Zhao, 2013; W Li, Zhang, et al, 2016; Mayola et al, 2011). Recently, another withanolide‐type compound named physapubenolide was encountered in Physalis minima L., Wang et al found that in vivo growth inhibition of human malignant melanoma cells implanted in BALB/c mice by physapubenolide administration (10 mg/kg, i.p., for 10 days) was accompanied by reduced cell proliferation and migration, and increased apoptosis (H‐Y Wang, Yu, et al, 2022). It is reported that a withanolide of 17β‐hydroxywithanolide class, physachenolide C had shown excellent performance in treating melanoma.…”

“…The main mechanisms involved in cancer cell invasion are associated with EMT, degradation of exocellular matrix, migration, and activating signaling pathways (Friedl & Mayor, 2017; Thiery, 2002). Withaferin A, withalongolide A, withalongolide A 4,19,27‐triacetate, withanone, physapubescin B, physapubenolide, withalongolide A, tubocapsanolide A, and 3‐azidowithaferin A were specified with properties of inhibiting invasion and metastasis through multiple pathways and steps (Garg et al, 2020; Rah et al, 2012; Subramanian et al, 2018; Thaiparambil et al, 2011; H‐Y Wang, Yu, et al, 2022; Xiang et al, 2021; Zhao et al, 2017).…”

“…By modulating the expression of these proteins and molecules, it is possible to restrict the further progression of EMT, thereby restraining the invasion and metastasis of cancer. Withaferin A (Chaudhary et al, 2019; Kyakulaga et al, 2018), physapubescin B (Zhao et al, 2017), physapubenolide (H‐Y Wang, Yu, et al, 2022), tubocapsanolide A (Xiang et al, 2021), and 3‐azidowithaferin A (ur Rasool et al, 2016) were proposed to achieve this by upregulating E‐cadherin and downregulating N‐cadherin proteins. Withaferin A (Makol et al, 2020; Zhao et al, 2018), physapubescin (L Chen, Xia, He, et al, 2016), and physapubescin B (Zhao et al, 2017) are claimed to decrease vimentin and reverse the EMT phenotype profiles in various cancer types.…”

“…4β‐hydroxywithanolide E inhibits the stability and nuclear translocation of β‐catenin concomitant with the downregulation of its total level of colorectal cancer both in vivo and in vitro (Ye et al, 2019). Besides, withaferin A and physapubenolide were proven to suppressβ‐catenin expression as well (H‐Y Wang, Yu, et al, 2022; Jung et al, 2022). Jung et al (2022) have demonstrated that β‐catenin can sensitize colorectal cancer cell lines to apoptosis and autophagy induced by withaferin A.…”

Chantriolides F–P, Highly Oxidized Withanolides with Hepatoprotective Activity from Tacca chantrieri

“…In addition, withanolides were reported from the Taccaceae, Myrtaceae, Labiataem, Dioscoreaceae, and Asteraceae families, and from the soft corals (marine source) as well. Due to their unique structures [ 1 , 2 , 3 , 4 , 5 ] and diverse biological activities [ 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 ], withanolides have captured extensive attention, and over the past decade, more than 500 new withanolides of natural origin have been discovered [ 14 , 15 , 16 ].…”