Antrodia salmonea induces apoptosis and enhances cytoprotective autophagy in colon cancer cells

Aging (Albany NY). 2021 May 24;13(12):15964-15989. doi: 10.18632/aging.203019. Epub 2021 May 24.

Abstract

A traditional Chinese medicinal fungus, Antrodia salmonea (AS), with antioxidant properties is familiar in Taiwan but anti-cancer activity of AS in human colon cancer is ambiguous. Hence, we explored the anti-cancer activity of AS in colon cancer cells. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay revealed that AS showed a remarkable effect on cell viability in colon cancer cells; SW620, HCT116, and HT29. Annexin V/propidium iodide (PI) stained cells indicated that AS induced both early/late apoptosis in SW620 cells. Additionally, cells treated with AS induced caspase-3 activation, poly (ADP-ribose) polymerase (PARP) cleavage, mitochondrial dysfunction, and Bcl-2 associated X (Bax)/B-cell lymphoma (Bcl-2) dysregulation. Microtubule- associated protein 1A/1B-light chain 3B (LC3-II) accumulation, sequestosome 1 (p62/SQSTM1) activation, autophagy related 4B cysteine peptidase (ATG4B) inactivation, acidic vesicular organelles (AVOs) formation, and Beclin-1/Bcl-2 dysregulation revealed that AS-induced autophagy. Interestingly, cells pretreated with 3-methyladenine (3-MA) strengthened AS-induced caspase-3/apoptosis. Suppression of apoptosis by z-Val-Ala-Asp fluoromethyl ketone (Z-VAD-FMK) did not however block AS-induced autophagy, suggesting that autophagy was not attenuated by the AS-induced apoptosis. Application of N-acetylcysteine (NAC) prevented AS-induced cell death, caspase-3 activation, LC3-II accumulation, and AVOs formation, indicating that AS-induced apoptosis and autophagy was mediated by reactive oxygen species (ROS). Furthermore, AS-induced cytoprotective autophagy and apoptosis through extracellular signal-regulated kinase (ERK) signaling cascades. Moreover, in vivo data disclosed that AS inhibited colitis-associated tumorigenesis in azoxymethane (AOM)-dextran sodium sulphate (DSS)-treated mice. For the first time, we report the anti-cancer properties of this potentially advantageous mushroom for the treatment of human colon cancer.

Keywords: Antrodia salmonea; ROS; apoptosis; autophagy; colon cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine / analogs & derivatives
  • Adenine / pharmacology
  • Animals
  • Apoptosis* / drug effects
  • Autophagy* / drug effects
  • Azoxymethane
  • Beclin-1 / metabolism
  • Carcinogenesis / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Chloroquine / pharmacology
  • Colitis / chemically induced
  • Colitis / complications
  • Colonic Neoplasms / etiology
  • Colonic Neoplasms / pathology*
  • Cytoprotection* / drug effects
  • Dextran Sulfate
  • Disease Progression
  • Humans
  • Inflammation / pathology
  • MAP Kinase Signaling System / drug effects
  • Mice
  • Mice, Inbred ICR
  • Microtubule-Associated Proteins / metabolism
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • NF-kappa B / metabolism
  • Organ Size / drug effects
  • Polyporales / chemistry*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Reactive Oxygen Species / metabolism
  • TOR Serine-Threonine Kinases / metabolism
  • bcl-2-Associated X Protein / metabolism

Substances

  • Beclin-1
  • MAP1LC3A protein, human
  • Microtubule-Associated Proteins
  • NF-kappa B
  • Reactive Oxygen Species
  • bcl-2-Associated X Protein
  • 3-methyladenine
  • Chloroquine
  • Dextran Sulfate
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • Adenine
  • Azoxymethane

Supplementary concepts

  • Taiwanofungus salmoneus