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

Cell Death Dis. 2020 Sep 2;11(8):717. doi: 10.1038/s41419-020-02924-w.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 4 / metabolism
  • Angelica
  • Astragalus Plant
  • Autophagic Cell Death / drug effects
  • Autophagy / drug effects*
  • Beclin-1
  • Cell Hypoxia / drug effects
  • Cell Hypoxia / physiology
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Endoplasmic Reticulum Stress / drug effects
  • Histocompatibility Antigens / metabolism
  • Histone-Lysine N-Methyltransferase / metabolism
  • Humans
  • Membrane Proteins / metabolism
  • Plant Extracts / metabolism
  • Plant Extracts / pharmacology*
  • Proto-Oncogene Proteins / metabolism
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction / drug effects
  • Stomach Neoplasms / metabolism*
  • Trichosanthes

Substances

  • ATF4 protein, human
  • BNIP3 protein, human
  • Beclin-1
  • Histocompatibility Antigens
  • Membrane Proteins
  • Plant Extracts
  • Proto-Oncogene Proteins
  • SH003 extract
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Activating Transcription Factor 4
  • EHMT2 protein, human
  • Histone-Lysine N-Methyltransferase