(20S) Ginsenoside Rh2 Exerts Its Anti-Tumor Effect by Disrupting the HSP90A-Cdc37 System in Human Liver Cancer Cells

Abstract

(20S) ginsenoside Rh2 (G-Rh2), a major bioactive metabolite of ginseng, effectively inhibits the survival and proliferation of human liver cancer cells. However, its molecular targets and working mechanism remain largely unknown. Excitingly, we screened out heat shock protein 90 alpha (HSP90A), a key regulatory protein associated with liver cancer, as a potential target of (20S) G-Rh2 by phage display analysis and mass spectrometry. The molecular docking and thermal shift analyses demonstrated that (20S) G-Rh2 directly bound to HSP90A, and this binding was confirmed to inhibit the interaction between HSP90A and its co-chaperone, cell division cycle control protein 37 (Cdc37). It is well-known that the HSP90A-Cdc37 system aids in the folding and maturation of cyclin-dependent kinases (CDKs). As expected, CDK4 and CDK6, the two G0-G1 phase promoting kinases as well as CDK2, a key G1-S phase transition promoting kinase, were significantly downregulated with (20S) G-Rh2 treatment, and these downregulations were mediated by the proteasome pathway. In the same condition, the cell cycle was arrested at the G0-G1 phase and cell growth was inhibited significantly by (20S) G-Rh2 treatment. Taken together, this study for the first time reveals that (20S) G-Rh2 exerts its anti-tumor effect by targeting HSP90A and consequently disturbing the HSP90A-Cdc37 chaperone system. HSP90A is frequently overexpressed in human hepatoma cells and the higher expression is closely correlated to the poor prognosis of liver cancer patients. Thus, (20S) G-Rh2 might become a promising alternative drug for liver cancer therapy.

A network pharmacology approach to explore and validate the potential targets of ginsenoside on osteoporosis

“…Some examples have demonstrated that different ginsenosides active ingredients have anti-tumor effect in various cancers. 41 , 42 However, gisenosides and osteoclast differentiation also have a strong correlation. Gisenosides prevent osteoporosis by inhibiting osteoclast differentiation.…”

Annexin A2: The diversity of pathological effects in tumorigenesis and immune response

“…80,81 (20S) ginsenoside Rh2 has been identified as a major active substance of ginseng and has significant anticancer activity. 82 In 2020, Wang et al found that ANXA2 interacted with NF-κB p50 subunit and facilitated NF-κB activation to boost the expression of mesenchymal-like genes, cell motility and EMT transition in triple-negative breast cancer cells 76 (Figure 1).…”

“…The lncRNA‐MUF colocalize with ANXA2 in the cytoplasm of HCC cells to promote ANXA2 combination with glycogen synthase kinase 3β (GSK3β), and accelerate the EMT pathway activation through Wnt/β‐catenin signaling 80,81 . (20S) ginsenoside Rh2 has been identified as a major active substance of ginseng and has significant anticancer activity 82 . In 2020, Wang et al found that ANXA2 interacted with NF‐κB p50 subunit and facilitated NF‐κB activation to boost the expression of mesenchymal‐like genes, cell motility and EMT transition in triple‐negative breast cancer cells 76 (Figure 1).…”

Cancer treatment: from traditional Chinese herbal medicine to the liposome delivery system

“…The bioactive compounds in ginseng include approximately 30 triterpene glycosides, called ginsenosides (Rb1, Rb2, Rg1, Rg2, Rg3, Rc, Rd, Re, Rh1, Rh2, etc.) [135,136]. Among the glycosides, Rg3, Rd, and Rh2 have anti-tumor activity.…”