Compound K Induces Endoplasmic Reticulum Stress and Apoptosis in Human Liver Cancer Cells by Regulating STAT3

Abstract

The ginsenoside compound K (20-O-β-d-glucopyranosyl-20(S)-protopanaxadiol; CK) is an intestinal bacterial metabolite of ginseng protopanaxadiol saponin that has been reported to induce apoptosis in many cancer cells; however, the precise mechanisms of its activity in human hepatocellular carcinoma (HCC) cells remain unclear. Herein, we demonstrated that CK inhibited the growth and colony formation of HepG2 and SMMC-7721 cells, phenotypes that were mediated by inducing apoptosis. Meanwhile, CK showed lower toxicity in normal hepatoma cells. After treating HepG2 and SMMC-7721 cells with CK, p-STAT3 levels decreased, the three branches of the unfolded protein response were activated, and levels of endoplasmic reticulum stress (ERS)-related proteins were increased. We also revealed that CK decreased the DNA-binding capacity of STAT3. Moreover, silencing STAT3 with CRISPR/Cas9 technology enhanced CK-induced ERS and apoptosis. Finally, we showed that CK inhibited the growth of liver cancer xenografts with little toxicity. Mice bearing human HCC xenografts that were treated with CK showed increased GRP78 expression and decreased p-STAT3 levels. Taken together, these data showed that CK induced ERS and apoptosis by inhibiting p-STAT3 in human liver cancer cells; thus, CK might be a potential therapeutic candidate for human HCC.

Ginsenoside Compound K: Insights into Recent Studies on Pharmacokinetics and Health-Promoting Activities

“…Furthermore, a substantial reduction in tumor proliferation was observed in the CK-supplemented mice group [ 84 ]. Also, CK induced apoptosis and ERS in liver cancer cells and xenografted mice by modulating signal transducers and activators of transcription-3 (STAT3) activation [ 85 ]. Another study showed for the first time that CK targeted annexin A2, which leads to inhibition of NF-κB [ 86 ].…”

Ginsenosides: the need to move forward from bench to clinical trials

“…There have been a large number of studies investigating the pharmacological effect of ginseng and ginsenosides and the underlying molecular mechanisms. Ginseng and ginsenosides have been reported to play critical roles in preventing and treating many human diseases, including cancers and neuronal, cardiovascular, inflammatory, and metabolic diseases [6], [7], [8], [9], [10]; furthermore, the molecular mechanisms of their pharmacological actions are due to the diverse biological activities of the natural products, such as proapoptosis, antiangiogenesis, stimulation of the central nervous system, antiinflammatory responses, protective effects on DNA, and chemoprophylaxis [6], [9], [17], [18], [19], [20], [21].…”

Combination therapy of ginsenoside compound K and methotrexate was efficient in elimination of anaemia and reduction of disease activity in adjuvant-induced arthritis rats

“… 2019 ; Zhang et al. 2018 ). Ginsenoside compound K (CK) comes from the degradation of products of natural diol-type ginsenosides (Rb1, Rb2 and Rc) in the human intestinal tract, and is the main form of ginsenoside absorption and activity in vivo .…”

“…Ginseng has been used as medicine and health food for a long time. A large number of studies have found that ginsenosides play a pharmacological role in immune regulation, antiinflammation, antioxidation and antitumor (Zeng et al 2018;Jung et al 2019;Zhang et al 2018). Ginsenoside compound K (CK) comes from the degradation of products of natural dioltype ginsenosides (Rb1, Rb2 and Rc) in the human intestinal tract, and is the main form of ginsenoside absorption and activity in vivo.…”