Short-chain fatty acids induced autophagy serves as an adaptive strategy for retarding mitochondria-mediated apoptotic cell death

Cell Death Differ. 2011 Apr;18(4):602-18. doi: 10.1038/cdd.2010.117. Epub 2010 Oct 8.

Abstract

Short-chain fatty acids (SCFAs) are the major by-products of bacterial fermentation of undigested dietary fibers in the large intestine. SCFAs, mostly propionate and butyrate, inhibit proliferation and induce apoptosis in colon cancer cells, but clinical trials had mixed results regarding the anti-tumor activities of SCFAs. Herein we demonstrate that propionate and butyrate induced autophagy in human colon cancer cells to dampen apoptosis whereas inhibition of autophagy potentiated SCFA induced apoptosis. Colon cancer cells, after propionate treatment, exhibited extensive characteristics of autophagic proteolysis: increased LC3-I to LC3-II conversion, acidic vesicular organelle development, and reduced p62/SQSTM1 expression. Propionate-induced autophagy was associated with decreased mTOR activity and enhanced AMP kinase activity. The elevated AMPKα phosphorylation was associated with cellular ATP depletion and overproduction of reactive oxygen species due to mitochondrial dysfunction involving the induction of MPT and loss of Δψ. In this context, mitochondria biogenesis was initiated to recover cellular energy homeostasis. Importantly, when autophagy was prevented either pharmacologically (3-MA or chloroquine) or genetically (knockdown of ATG5 or ATG7), the colon cancer cells became sensitized toward propionate-induced apoptosis through activation of caspase-7 and caspase-3. The observations indicate that propionate-triggered autophagy serves as an adaptive strategy for retarding mitochondria-mediated apoptotic cell death, whereas application of an autophagy inhibitor (Chloroquine) is expected to enhance the therapeutic efficacy of SCFAs in inducing colon tumor cell apoptosis.

MeSH terms

  • AMP-Activated Protein Kinases / metabolism
  • Adaptor Proteins, Signal Transducing / metabolism
  • Adenylate Kinase / metabolism
  • Apoptosis*
  • Autophagy*
  • Autophagy-Related Protein 5
  • Autophagy-Related Protein 7
  • Butyrates / toxicity
  • Caspase 3 / metabolism
  • Caspase 7 / metabolism
  • Cell Line, Tumor
  • Fatty Acids, Volatile / toxicity*
  • Humans
  • Microtubule-Associated Proteins / antagonists & inhibitors
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • Mitochondria / metabolism*
  • Phosphorylation
  • Propionates / toxicity
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Sequestosome-1 Protein
  • Signal Transduction
  • TOR Serine-Threonine Kinases / metabolism
  • Ubiquitin-Activating Enzymes / antagonists & inhibitors
  • Ubiquitin-Activating Enzymes / genetics
  • Ubiquitin-Activating Enzymes / metabolism

Substances

  • ATG5 protein, human
  • Adaptor Proteins, Signal Transducing
  • Autophagy-Related Protein 5
  • Butyrates
  • Fatty Acids, Volatile
  • Microtubule-Associated Proteins
  • Propionates
  • RNA, Small Interfering
  • SQSTM1 protein, human
  • Sequestosome-1 Protein
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • AMP-Activated Protein Kinases
  • Adenylate Kinase
  • Caspase 3
  • Caspase 7
  • Atg7 protein, human
  • Autophagy-Related Protein 7
  • Ubiquitin-Activating Enzymes