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Ginsenoside Rh2 Induces HeLa Apoptosis through Upregulating Endoplasmic Reticulum Stress-Related and Downstream Apoptotic Gene Expression

Cervical cancer is a common gynecological malignancy afflicting women all over the world. Ginsenoside Rh2 (GRh2), especially 20(S)-GRh2, is a biologically active component in the natural plant ginseng, which can exhibit anticancer effects. Here, we aimed to investigate the effect of 20(S)-GRh2 on ce...

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Autores principales: Liu, Ying, Wang, Xinran, Qiao, Juhui, Wang, Jiawen, Jiang, Leilei, Wang, Chenxi, Yu, Shiting, Zhang, Peiguang, Zhao, Daqing, Fan, Meiling, Liu, Meichen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9699401/
https://www.ncbi.nlm.nih.gov/pubmed/36431966
http://dx.doi.org/10.3390/molecules27227865
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author Liu, Ying
Wang, Xinran
Qiao, Juhui
Wang, Jiawen
Jiang, Leilei
Wang, Chenxi
Yu, Shiting
Zhang, Peiguang
Zhao, Daqing
Fan, Meiling
Liu, Meichen
author_facet Liu, Ying
Wang, Xinran
Qiao, Juhui
Wang, Jiawen
Jiang, Leilei
Wang, Chenxi
Yu, Shiting
Zhang, Peiguang
Zhao, Daqing
Fan, Meiling
Liu, Meichen
author_sort Liu, Ying
collection PubMed
description Cervical cancer is a common gynecological malignancy afflicting women all over the world. Ginsenoside Rh2 (GRh2), especially 20(S)-GRh2, is a biologically active component in the natural plant ginseng, which can exhibit anticancer effects. Here, we aimed to investigate the effect of 20(S)-GRh2 on cervical cancer and elucidate the underlying mechanism through RNA-seq. In this study, the CCK-8 assay showed that 20(S)-GRh2 inhibited HeLa cell viability in a time- and dose-dependent manner. Caspase 3 activity and Annexin V staining results showed that 20(S)-GRh2 induced apoptosis of HeLa cells. Gene function enrichment analysis revealed that the biological process gene ontology (GO) terms were associated with the apoptotic signaling pathway. Biological process GO terms’ similarity network indicated that apoptosis might be from endoplasmic reticulum stress (ERs). Kyoto Encyclopedia of Genes and Genomes enrichment analysis revealed that 20(S)-GRh2 primarily modulates apoptosis pathway genes. Combined protein–protein interaction network, hub gene screening, and qPCR validation data showed that ERs-related genes (ATF4 and DDIT3) and the downstream apoptotic genes (JUN, FOS, BBC3, and PMAIP1) were potential novel targets of 20(S)-GRh2-inducing cervical cancer cell apoptosis. Differential transcript usage analysis indicated that DDIT3 is also a differential transcript and its usage of the isoform (ENST00000552740.5) was reduced by 20(S)-GRh2. Molecular docking suggested that 20(S)-GRh2 binds to the targets (ATF4, DDIT3, JUN, FOS, BBC3, and PMAIP1) with high affinity. In conclusion, our findings indicated that 20(S)-GRh2 might promote ERs-related apoptosis of cervical cancer cells by regulating the DDIT3-based targets’ signal pathway. The role of 20(S)-GRh2 at the transcriptome level provides novel targets and evidence for the treatment of cervical cancer.
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spelling pubmed-96994012022-11-26 Ginsenoside Rh2 Induces HeLa Apoptosis through Upregulating Endoplasmic Reticulum Stress-Related and Downstream Apoptotic Gene Expression Liu, Ying Wang, Xinran Qiao, Juhui Wang, Jiawen Jiang, Leilei Wang, Chenxi Yu, Shiting Zhang, Peiguang Zhao, Daqing Fan, Meiling Liu, Meichen Molecules Article Cervical cancer is a common gynecological malignancy afflicting women all over the world. Ginsenoside Rh2 (GRh2), especially 20(S)-GRh2, is a biologically active component in the natural plant ginseng, which can exhibit anticancer effects. Here, we aimed to investigate the effect of 20(S)-GRh2 on cervical cancer and elucidate the underlying mechanism through RNA-seq. In this study, the CCK-8 assay showed that 20(S)-GRh2 inhibited HeLa cell viability in a time- and dose-dependent manner. Caspase 3 activity and Annexin V staining results showed that 20(S)-GRh2 induced apoptosis of HeLa cells. Gene function enrichment analysis revealed that the biological process gene ontology (GO) terms were associated with the apoptotic signaling pathway. Biological process GO terms’ similarity network indicated that apoptosis might be from endoplasmic reticulum stress (ERs). Kyoto Encyclopedia of Genes and Genomes enrichment analysis revealed that 20(S)-GRh2 primarily modulates apoptosis pathway genes. Combined protein–protein interaction network, hub gene screening, and qPCR validation data showed that ERs-related genes (ATF4 and DDIT3) and the downstream apoptotic genes (JUN, FOS, BBC3, and PMAIP1) were potential novel targets of 20(S)-GRh2-inducing cervical cancer cell apoptosis. Differential transcript usage analysis indicated that DDIT3 is also a differential transcript and its usage of the isoform (ENST00000552740.5) was reduced by 20(S)-GRh2. Molecular docking suggested that 20(S)-GRh2 binds to the targets (ATF4, DDIT3, JUN, FOS, BBC3, and PMAIP1) with high affinity. In conclusion, our findings indicated that 20(S)-GRh2 might promote ERs-related apoptosis of cervical cancer cells by regulating the DDIT3-based targets’ signal pathway. The role of 20(S)-GRh2 at the transcriptome level provides novel targets and evidence for the treatment of cervical cancer. MDPI 2022-11-14 /pmc/articles/PMC9699401/ /pubmed/36431966 http://dx.doi.org/10.3390/molecules27227865 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Liu, Ying
Wang, Xinran
Qiao, Juhui
Wang, Jiawen
Jiang, Leilei
Wang, Chenxi
Yu, Shiting
Zhang, Peiguang
Zhao, Daqing
Fan, Meiling
Liu, Meichen
Ginsenoside Rh2 Induces HeLa Apoptosis through Upregulating Endoplasmic Reticulum Stress-Related and Downstream Apoptotic Gene Expression
title Ginsenoside Rh2 Induces HeLa Apoptosis through Upregulating Endoplasmic Reticulum Stress-Related and Downstream Apoptotic Gene Expression
title_full Ginsenoside Rh2 Induces HeLa Apoptosis through Upregulating Endoplasmic Reticulum Stress-Related and Downstream Apoptotic Gene Expression
title_fullStr Ginsenoside Rh2 Induces HeLa Apoptosis through Upregulating Endoplasmic Reticulum Stress-Related and Downstream Apoptotic Gene Expression
title_full_unstemmed Ginsenoside Rh2 Induces HeLa Apoptosis through Upregulating Endoplasmic Reticulum Stress-Related and Downstream Apoptotic Gene Expression
title_short Ginsenoside Rh2 Induces HeLa Apoptosis through Upregulating Endoplasmic Reticulum Stress-Related and Downstream Apoptotic Gene Expression
title_sort ginsenoside rh2 induces hela apoptosis through upregulating endoplasmic reticulum stress-related and downstream apoptotic gene expression
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9699401/
https://www.ncbi.nlm.nih.gov/pubmed/36431966
http://dx.doi.org/10.3390/molecules27227865
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