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Stigmasterol Simultaneously Induces Apoptosis and Protective Autophagy by Inhibiting Akt/mTOR Pathway in Gastric Cancer Cells

BACKGROUND: Stigmasterol (SS) has been proven to possess potential anticancer activities in several cancer cell lines, but its molecular mechanism is still unknown. Thus, we investigated whether SS has the capabilities of inducing autophagy and its molecular mechanisms in gastric cancer cells. METHO...

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Autores principales: Zhao, Huange, Zhang, Xian, Wang, Min, Lin, Yingying, Zhou, Songlin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940753/
https://www.ncbi.nlm.nih.gov/pubmed/33708631
http://dx.doi.org/10.3389/fonc.2021.629008
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author Zhao, Huange
Zhang, Xian
Wang, Min
Lin, Yingying
Zhou, Songlin
author_facet Zhao, Huange
Zhang, Xian
Wang, Min
Lin, Yingying
Zhou, Songlin
author_sort Zhao, Huange
collection PubMed
description BACKGROUND: Stigmasterol (SS) has been proven to possess potential anticancer activities in several cancer cell lines, but its molecular mechanism is still unknown. Thus, we investigated whether SS has the capabilities of inducing autophagy and its molecular mechanisms in gastric cancer cells. METHODS: We used CCK8 assay, clone formation assay, and EdU proliferation assay to assess the effects of SS on cell proliferation in SGC-7901 and MGC-803 cells in vitro, and its inhibition on the tumor growth of gastric cancer was observed in vivo. Apoptosis induced by SS was demonstrated using Hoechst and TUNEL staining, annexin V-FITC/PI assay. Immunofluorescence staining is used to detect the formation of autophagosomes triggered by SS. Apoptosis and autophagy related proteins were analyzed by western blot. RESULTS: The results indicated that SS treatment inhibited cell proliferation in SGC-7901 and MGC-803 cells. Furthermore, SS treatment induced apoptosis and autophagy by blocking Akt/mTOR signaling pathway. The pretreatment with the Akt inhibitor MK-2206 could promote apoptosis and autophagy induced by SS, predicting that Akt/mTOR pathway is involved in SS-induced apoptosis and autophagy. In addition, blockade of autophagy with 3-MA (an inhibitor of autophagy) enhanced SS-induced apoptosis in SGC-7901 and MGC-803 cells, implying that autophagy mediated by SS plays a cytoprotective role against apoptosis. Finally, an in vivo study demonstrated that tumor growth of gastric cancer was suppressed by SS in a xenograft model. CONCLUSION: Our findings illustrate for the first time that SS simultaneously induces apoptosis and protective autophagy by inhibiting Akt/mTOR pathway in gastric cancer cells, and SS may become a potential anticancer drug in treating gastric cancer in the future.
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spelling pubmed-79407532021-03-10 Stigmasterol Simultaneously Induces Apoptosis and Protective Autophagy by Inhibiting Akt/mTOR Pathway in Gastric Cancer Cells Zhao, Huange Zhang, Xian Wang, Min Lin, Yingying Zhou, Songlin Front Oncol Oncology BACKGROUND: Stigmasterol (SS) has been proven to possess potential anticancer activities in several cancer cell lines, but its molecular mechanism is still unknown. Thus, we investigated whether SS has the capabilities of inducing autophagy and its molecular mechanisms in gastric cancer cells. METHODS: We used CCK8 assay, clone formation assay, and EdU proliferation assay to assess the effects of SS on cell proliferation in SGC-7901 and MGC-803 cells in vitro, and its inhibition on the tumor growth of gastric cancer was observed in vivo. Apoptosis induced by SS was demonstrated using Hoechst and TUNEL staining, annexin V-FITC/PI assay. Immunofluorescence staining is used to detect the formation of autophagosomes triggered by SS. Apoptosis and autophagy related proteins were analyzed by western blot. RESULTS: The results indicated that SS treatment inhibited cell proliferation in SGC-7901 and MGC-803 cells. Furthermore, SS treatment induced apoptosis and autophagy by blocking Akt/mTOR signaling pathway. The pretreatment with the Akt inhibitor MK-2206 could promote apoptosis and autophagy induced by SS, predicting that Akt/mTOR pathway is involved in SS-induced apoptosis and autophagy. In addition, blockade of autophagy with 3-MA (an inhibitor of autophagy) enhanced SS-induced apoptosis in SGC-7901 and MGC-803 cells, implying that autophagy mediated by SS plays a cytoprotective role against apoptosis. Finally, an in vivo study demonstrated that tumor growth of gastric cancer was suppressed by SS in a xenograft model. CONCLUSION: Our findings illustrate for the first time that SS simultaneously induces apoptosis and protective autophagy by inhibiting Akt/mTOR pathway in gastric cancer cells, and SS may become a potential anticancer drug in treating gastric cancer in the future. Frontiers Media S.A. 2021-02-23 /pmc/articles/PMC7940753/ /pubmed/33708631 http://dx.doi.org/10.3389/fonc.2021.629008 Text en Copyright © 2021 Zhao, Zhang, Wang, Lin and Zhou http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Zhao, Huange
Zhang, Xian
Wang, Min
Lin, Yingying
Zhou, Songlin
Stigmasterol Simultaneously Induces Apoptosis and Protective Autophagy by Inhibiting Akt/mTOR Pathway in Gastric Cancer Cells
title Stigmasterol Simultaneously Induces Apoptosis and Protective Autophagy by Inhibiting Akt/mTOR Pathway in Gastric Cancer Cells
title_full Stigmasterol Simultaneously Induces Apoptosis and Protective Autophagy by Inhibiting Akt/mTOR Pathway in Gastric Cancer Cells
title_fullStr Stigmasterol Simultaneously Induces Apoptosis and Protective Autophagy by Inhibiting Akt/mTOR Pathway in Gastric Cancer Cells
title_full_unstemmed Stigmasterol Simultaneously Induces Apoptosis and Protective Autophagy by Inhibiting Akt/mTOR Pathway in Gastric Cancer Cells
title_short Stigmasterol Simultaneously Induces Apoptosis and Protective Autophagy by Inhibiting Akt/mTOR Pathway in Gastric Cancer Cells
title_sort stigmasterol simultaneously induces apoptosis and protective autophagy by inhibiting akt/mtor pathway in gastric cancer cells
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940753/
https://www.ncbi.nlm.nih.gov/pubmed/33708631
http://dx.doi.org/10.3389/fonc.2021.629008
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