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The identification of molecular target of (20S) ginsenoside Rh2 for its anti-cancer activity.

ABSTRACT: The 20S ginsenoside Rh2 (G-Rh2) effectively inhibits cancer cell growth and survival in both animal models and cell lines. However, its molecular targets and mechanism of action remain largely unknown. By screening for molecules that interact with (20S)G-Rh2 in a phage display assay, we have identified Annexin A2 as a potential target that mediates its anti-cancer activity. Isothermal titration calorimetry and a cellular thermal shift assay demonstrated that (20S)G-Rh2 directly bound to either recombinant or intracellular Annexin A2. This binding inhibited the interaction between Annexin A2 and the NF-?B p50 subunit, which attenuated the nuclear translocations of NF-?B p50 subunit and reduced the transactivation activity of NF-?B. Correspond to this result, (20S)G-Rh2 treatment significantly down-regulated the expression of IAPs (inhibitors of apoptosis), the well-established NF-?B targets that promote cell survival. Moreover, (20S)G-Rh2 synergized with Annexin A2 inactivation to promote apoptosis. Taken together, this study for the first time suggests a cellular target and a molecular pathway by which (20S)G-Rh2 inhibits cancer cell growth. As over-expression of Annexin A2 was evident in human hepatoma, (20S)G-Rh2 might be a promising natural compound for targeted liver cancer therapy.

SUBMITTER: Wang YS

PROVIDER: S-EPMC5622071 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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The identification of molecular target of (20S) ginsenoside Rh2 for its anti-cancer activity.

Wang Yu-Shi YS Lin Yingjia Y Li He H Li Yang Y Song Zhiguang Z Jin Ying-Hua YH

Scientific reports 20170929 1

The 20S ginsenoside Rh2 (G-Rh2) effectively inhibits cancer cell growth and survival in both animal models and cell lines. However, its molecular targets and mechanism of action remain largely unknown. By screening for molecules that interact with (20S)G-Rh2 in a phage display assay, we have identified Annexin A2 as a potential target that mediates its anti-cancer activity. Isothermal titration calorimetry and a cellular thermal shift assay demonstrated that (20S)G-Rh2 directly bound to either r ...[more]

PMID: 28963461

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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.

Dataset Information

The identification of molecular target of (20S) ginsenoside Rh2 for its anti-cancer activity.

Publications

The identification of molecular target of (20S) ginsenoside Rh2 for its anti-cancer activity.

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