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.
Highlights
Ginseng is a valuable medicinal herb in Asian countries that has been used for centuries as a panacea to enhance stamina and promote longevity [1,2]
To examine the effects of CK on the growth of human hepatocellular carcinoma (HCC) cells, we treated four human liver cancer cell lines (HepG2, SMMC-7721, Hep3B and Huh7) and one normal liver cell line (L02) with CK at concentrations ranging from 20–60 μM for 48 h and MTT
The results showed that CK effectively decreased the growth of liver cancer cells in a dose-dependent manner (Figure 1B)
Summary
Ginseng is a valuable medicinal herb in Asian countries that has been used for centuries as a panacea to enhance stamina and promote longevity [1,2]. Ginsenosides, or compounds extracted from ginseng, are the major components of ginseng and exhibit useful pharmacological activities including anti-inflammatory, antitumor, anti-dementia and anti-allergic effects [3,4,5]. The signal transducers and activators of transcription (STAT) family includes STAT1, 2, 3, 4, 5a, 5b and 6, and is closely related to cell growth and differentiation [11]. STAT3 was observed to be hyperactive in cancer where it promotes tumorigenesis by enhancing cell proliferation and angiogenesis in various malignant tumors including liver, lung, and breast cancers [12,13,14]. When phosphorylated (activated), STAT3 translocates into the nucleus and binds specific DNA sequences to promote target gene transcription. The downstream targets of STAT3 include many gene products, such
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