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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Bibliographic Details
Published in:Cell death & disease 2020-09, Vol.11 (8), p.717-717, Article 717
Main Authors: Kim, Tae Woo, Cheon, Chunhoo, Ko, Seong-Gyu
Format: Article
Language:English
Subjects:
Activating Transcription Factor 4 - metabolism
Angelica
Apoptosis
Astragalus Plant
Autophagic Cell Death - drug effects
Autophagy
Autophagy - drug effects
Bcl-2 protein
Beclin-1
BNIP3 protein
Cell activation
Cell death
Cell Hypoxia - drug effects
Cell Hypoxia - physiology
Cell Line, Tumor
Cell Survival - drug effects
Endoplasmic Reticulum Stress - drug effects
Gastric cancer
Histocompatibility Antigens - metabolism
Histone methyltransferase
Histone-Lysine N-Methyltransferase - metabolism
Humans
Hypoxia
Membrane Proteins - metabolism
Phagocytosis
Phosphorylation
Plant Extracts - metabolism
Plant Extracts - pharmacology
Proto-Oncogene Proteins - metabolism
Signal Transduction - drug effects
siRNA
Stat3 protein
STAT3 Transcription Factor - metabolism
Stomach Neoplasms - metabolism
Trichosanthes
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Summary: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.
ISSN:2041-4889
2041-4889
DOI:10.1038/s41419-020-02924-w