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SH003 activates autophagic cell death by activating ATF4 and inhibiting G9a under hypoxia in gastric cancer cells

In gastric cancer (GC), hypoxia is one of the greatest obstacles to cancer therapy. In this present study, we report that SH003, an herbal formulation, induces ER stress via PERK-ATF4-CHOP signaling in GC. SH003-mediated ER stress inhibits G9a, a histone methyltransferase, by reducing STAT3 phosphor...

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Autores principales: Kim, Tae Woo, Cheon, Chunhoo, Ko, Seong-Gyu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468158/
https://www.ncbi.nlm.nih.gov/pubmed/32879309
http://dx.doi.org/10.1038/s41419-020-02924-w
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author Kim, Tae Woo
Cheon, Chunhoo
Ko, Seong-Gyu
author_facet Kim, Tae Woo
Cheon, Chunhoo
Ko, Seong-Gyu
author_sort Kim, Tae Woo
collection PubMed
description In gastric cancer (GC), hypoxia is one of the greatest obstacles to cancer therapy. In this present study, we report that SH003, an herbal formulation, induces ER stress via PERK-ATF4-CHOP signaling in GC. SH003-mediated ER stress inhibits G9a, a histone methyltransferase, by reducing STAT3 phosphorylation and activates autophagy, indicating to the dissociation of Beclin-1 and autophagy initiation from Bcl-2/Beclin-1 complex. However, the inhibition of PERK and CHOP inhibited SH003-induced cell death and autophagy activation. Moreover, targeting autophagy using specific siRNAs of LC3B or p62 or the autophagy inhibitor 3-MA also inhibited SH003-induced cell death in GC. Interestingly, SH003 induces BNIP3-mediated autophagic cell death under hypoxia than normoxia in GC. These findings reveal that SH003-induced ER stress regulates BNIP3-induced autophagic cell death via inhibition of STAT3-G9a axis under hypoxia in GC. Therefore, SH003 may an important tumor therapeutic strategy under hypoxia-mediated chemo-resistance.
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spelling pubmed-74681582020-09-16 SH003 activates autophagic cell death by activating ATF4 and inhibiting G9a under hypoxia in gastric cancer cells Kim, Tae Woo Cheon, Chunhoo Ko, Seong-Gyu Cell Death Dis Article In gastric cancer (GC), hypoxia is one of the greatest obstacles to cancer therapy. In this present study, we report that SH003, an herbal formulation, induces ER stress via PERK-ATF4-CHOP signaling in GC. SH003-mediated ER stress inhibits G9a, a histone methyltransferase, by reducing STAT3 phosphorylation and activates autophagy, indicating to the dissociation of Beclin-1 and autophagy initiation from Bcl-2/Beclin-1 complex. However, the inhibition of PERK and CHOP inhibited SH003-induced cell death and autophagy activation. Moreover, targeting autophagy using specific siRNAs of LC3B or p62 or the autophagy inhibitor 3-MA also inhibited SH003-induced cell death in GC. Interestingly, SH003 induces BNIP3-mediated autophagic cell death under hypoxia than normoxia in GC. These findings reveal that SH003-induced ER stress regulates BNIP3-induced autophagic cell death via inhibition of STAT3-G9a axis under hypoxia in GC. Therefore, SH003 may an important tumor therapeutic strategy under hypoxia-mediated chemo-resistance. Nature Publishing Group UK 2020-09-02 /pmc/articles/PMC7468158/ /pubmed/32879309 http://dx.doi.org/10.1038/s41419-020-02924-w Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Kim, Tae Woo
Cheon, Chunhoo
Ko, Seong-Gyu
SH003 activates autophagic cell death by activating ATF4 and inhibiting G9a under hypoxia in gastric cancer cells
title SH003 activates autophagic cell death by activating ATF4 and inhibiting G9a under hypoxia in gastric cancer cells
title_full SH003 activates autophagic cell death by activating ATF4 and inhibiting G9a under hypoxia in gastric cancer cells
title_fullStr SH003 activates autophagic cell death by activating ATF4 and inhibiting G9a under hypoxia in gastric cancer cells
title_full_unstemmed SH003 activates autophagic cell death by activating ATF4 and inhibiting G9a under hypoxia in gastric cancer cells
title_short SH003 activates autophagic cell death by activating ATF4 and inhibiting G9a under hypoxia in gastric cancer cells
title_sort sh003 activates autophagic cell death by activating atf4 and inhibiting g9a under hypoxia in gastric cancer cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468158/
https://www.ncbi.nlm.nih.gov/pubmed/32879309
http://dx.doi.org/10.1038/s41419-020-02924-w
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