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(20S) Ginsenoside Rh2-Activated, Distinct Apoptosis Pathways in Highly and Poorly Differentiated Human Esophageal Cancer Cells.

ABSTRACT: Ginsenoside Rh2 (G-Rh2), a rare ginsenoside isolated from red ginseng, has considerable anti-cancer activity and induces apoptosis in a variety of cancer cells, but its activity in esophageal cancer cells is unclear. In this study, we examined the cytotoxic activity of (20S) G-Rh2 in highly differentiated esophageal squamous ECA109 cells and poorly differentiated esophageal squamous TE-13 cells. (20S) G-Rh2 exerted intense cytotoxicity in ECA109 and TE-13 cells with an IC50 of 2.9 and 3.7 μg/mL, respectively. After treatment with G-Rh2, Bcl-2, and Bcl-xL, the two main anti-apoptosis Bcl-2 family proteins upregulated, and Bax and Bak, the two key pro-apoptosis proteins translocated to mitochondria in both cell lines. At the same time, cytochrome c and Smac released from mitochondria, followed by caspase-9 activation, indicating that a mitochondria-mediated intrinsic apoptosis pathway was activated in both cell lines upon treatment with (20S) G-Rh2. It is noteworthy that (20S) G-Rh2 upregulated the transcription and protein expression of two death receptors, Fas and DR5, and subsequently activated Caspase-8 in the TE-13 cells but not in the ECA109 cells. Taken together, we demonstrated the potent anti-esophageal cancer cell activity of (20S) G-Rh2 and showed its working mechanism in two differentiated esophageal cancer cells, which can provide important evidence for developing an effective strategy for anti-esophageal cancer treatment.

SUBMITTER: Li H

PROVIDER: S-EPMC9457866 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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(20S) Ginsenoside Rh2-Activated, Distinct Apoptosis Pathways in Highly and Poorly Differentiated Human Esophageal Cancer Cells.

Li He H Han Chunxiao C Chen Chen C Han Guanghong G Li Yang Y

Molecules (Basel, Switzerland) 20220831 17

Ginsenoside Rh2 (G-Rh2), a rare ginsenoside isolated from red ginseng, has considerable anti-cancer activity and induces apoptosis in a variety of cancer cells, but its activity in esophageal cancer cells is unclear. In this study, we examined the cytotoxic activity of (20S) G-Rh2 in highly differentiated esophageal squamous ECA109 cells and poorly differentiated esophageal squamous TE-13 cells. (20S) G-Rh2 exerted intense cytotoxicity in ECA109 and TE-13 cells with an IC50 of 2.9 and 3.7 μg/mL, ...[more]

PMID: 36080369

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Project description:BackgroundCancer cells through autophagy-mediated recycling to meet the metabolic demands of growth and proliferation. The steroidal saponin 20(S)-ginsenoside Rh2 effectively inhibits the growth and survival of a variety of tumor cell lines and animal models, but the effects of Rh2 on autophagy remain elusive.MethodsCell viability was measured by CCK-8 (cell counting kit-8) assays. Apoptosis, ROS generation and mitochondrial membrane potential were analyzed by flow cytometry. Western blot analyses were used to determine changes in protein levels. Morphology of apoptotic cells and autophagosome accumulation were analyzed by DAPI staining and transmission electron microscopy. Autophagy induction was monitored by acidic vesicular organelle staining, EGFP-LC3 and mRFP-GFP-LC3 transfection. Atg7 siRNA and autophagy regulator was used to assess the effect of autophagy on apoptosis induced by G-Rh2.ResultsIn this study, we found that low concentration G-Rh2 attenuated cancer cell growth and induced apoptosis upon serum-free starvation. Caspase 3 inhibitors failed to block apoptosis in G-Rh2-treated cells, indicating a caspase-independent mechanism. G-Rh2-treated cells in serum-deprived conditions showed impaired mitochondrial function, increased release and nuclear translocation of apoptosis-inducing factor, but little changes in the mitochondrial and cytoplasmic distributions of cytochrome C. Annexin A2 overexpression in 293T cells inhibited G-Rh2-induced apoptosis under serum-starved conditions. Meanwhile, G-Rh2 reduced lysosomal activity and inhibited the fusion of autophagosome and lysosome, leading to a block of autophagic flux. Knockdown Atg7 significantly inhibited autophagy and triggered AIF-induced apoptosis in serm free condition. The autophagy inducer significantly decreased the apoptosis levels of G-Rh2-treated cells in serum-free conditions.ConclusionsUnder nutrient deficient conditions, G-Rh2 represses autophagy in cervical cancer cells and enhanced apoptosis through an apoptosis-inducing factor mediated pathway.

Project description:BackgroundDeregulation of Stat5 in the mammary gland of transgenic mice causes tumorigenesis. Poorly differentiated carcinoma and highly differentiated papillary adenocarcinoma tumors evolve. To distinguish the genes and elucidate the cellular processes and metabolic pathways utilized to preserve these phenotypes, gene-expression profiles were analyzed.MethodsMammary tumors were excised from transgenic mice carrying a constitutively active variant of Stat5, or a Stat5 variant lacking s transactivation domain. These tumors displayed either the carcinoma or the papillary adenocarcinoma phenotypes. cRNAs, prepared from each tumor were hybridized to an Affymetrix GeneChip(R) Mouse Genome 430A 2.0 array. Gene-ontology analysis, hierarchical clustering and biological-pathway analysis were performed to distinct the two types of tumors. Histopathology and immunofluorescence staining complemented the comparison between the tumor phenotypes.ResultsThe nucleus-cytoskeleton-plasma membrane axis is a major target for differential gene expression between phenotypes. In the carcinoma, stronger expression of genes coding for specific integrins, cytoskeletal proteins and calcium-binding proteins highlight cell-adhesion and motility features of the tumor cells. This is supported by the higher expression of genes involved in O-glycan synthesis, TGF-beta, activin, their receptors and Smad3, as well as the Notch ligands and members of the gamma-secretase complex that enable Notch nuclear localization. The Wnt pathway was also a target for differential gene expression. Higher expression of genes encoding the degradation complex of the canonical pathway and limited TCF expression in the papillary adenocarcinoma result in membranal accumulation of beta-catenin, in contrast to its nuclear translocation in the carcinoma. Genes involved in cell-cycle arrest at G1 and response to DNA damage were more highly expressed in the papillary adenocarcinomas, as opposed to favored G2/M regulation in the carcinoma tumors.ConclusionAt least six metabolic pathways support the morphological and functional differences between carcinomas and papillary adenocarcinomas. Differential gene-expression profiles favor cell adhesion, motility and proliferation in the carcinoma. Cell-cell contact, polarity, earlier cell-cycle arrest and DNA damage control are better displayed in the papillary adenocarcinoma.

Project description:IntroductionTriple-negative breast cancer (TNBC) is the most challenging subtype of breast cancer to treat. While previous studies have demonstrated that ginsenoside Rh2 induces apoptosis in TNBC cells, the specific molecular targets and underlying mechanisms remain poorly understood. This study aims to uncover the molecular mechanisms through which ginsenoside Rh2 regulates apoptosis and proliferation in TNBC, offering new insights into its therapeutic potential.MethodsNetwork analysis and transcriptome sequencing were utilized to explore the potential mechanisms of ginsenoside Rh2 in treating TNBC. In vivo imaging and immunohistochemistry were employed to examine the effects of ginsenoside Rh2 in a TNBC mouse model. Functional assays were conducted to assess the impact of ginsenoside Rh2 on TNBC cell behavior. Additionally, ELISA, Western blot, and quantitative real-time PCR were used to further investigate the mechanisms of ginsenoside Rh2-induced apoptosis in TNBC cells.ResultsThrough network analysis, 47 common targets were identified, and Gene Ontology (GO) enrichment analysis suggested that ginsenoside Rh2 may exert therapeutic effects in TNBC by influencing apoptosis, cell proliferation, and protein kinase activity. Both transcriptomic analysis and network analysis revealed the JAK/STAT signaling pathway as a key mechanism. Ginsenoside Rh2 inhibited tumor growth in TNBC mice and reduced the expression of IL- 6, IL-6R, STAT3, Bcl-2, and Bcl-xL in tumor tissues. The ability of ginsenoside Rh2 to inhibit TNBC cell proliferation was further confirmed by attenuating the activation of the IL-6/JAK2/STAT3 apoptosis pathway and reducing the expression of protein kinases AMPK-α1 and PKA-Cα.ConclusionBased on network analysis and experimental validation, our findings demonstrate that ginsenoside Rh2 regulates TNBC proliferation and apoptosis through suppression of the IL-6/JAK2/STAT3 pathway, both in vitro and in vivo. This comprehensive approach represents a significant advancement in understanding the therapeutic potential of ginsenoside Rh2 in treating TNBC.

Dataset Information

(20S) Ginsenoside Rh2-Activated, Distinct Apoptosis Pathways in Highly and Poorly Differentiated Human Esophageal Cancer Cells.

Publications

(20S) Ginsenoside Rh2-Activated, Distinct Apoptosis Pathways in Highly and Poorly Differentiated Human Esophageal Cancer Cells.

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