Autophagy is activated in colorectal cancer cells and contributes to the tolerance to nutrient deprivation

Cancer Res. 2007 Oct 15;67(20):9677-84. doi: 10.1158/0008-5472.CAN-07-1462.

Abstract

Several types of cancer cells, including colorectal cancer-derived cell lines, show austerity, the resistance to nutrient starvation, but exactly how cancer cells obtain energy sources under conditions in which their external nutrient supply is extremely limited remains to be clarified. Because autophagy is a catabolic process by which cells supply amino acids from self-digested organelles, cancer cells are likely to use autophagy to obtain amino acids as alternative energy sources. Amino acid deprivation-induced autophagy was assessed in DLD-1 and other colorectal cancer-derived cell lines. The autophagosome-incorporated LC3-II protein level increased after treatment with a combination of autolysosome inhibitors, which interferes with the consumption of autophagosomes. Autophagosome formation was also morphologically confirmed using ectopically expressed green fluorescent protein-LC3 fusion proteins in DLD-1 and SW480 cells. These data suggest that autophagosomes were actively produced and promptly consumed in colorectal cancer cells under nutrient starvation. Autolysosome inhibitors and 3-methyl adenine, which suppresses autophagosome formation, remarkably enhanced apoptosis under amino acid-deprived and glucose-deprived condition. Similar results were obtained in the cells with decreased ATG7 level by the RNA interference. These data suggest that autophagy is pivotal for the survival of colorectal cancer cells that have acquired austerity. Furthermore, autophagosome formation was seen only in the tumor cells but not in the adjacent noncancerous epithelial cells of colorectal cancer specimens. Taken together, autophagy is activated in colorectal cancers in vitro and in vivo, and autophagy may contribute to the survival of the cancer cells in their microenvironment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / metabolism*
  • Adenocarcinoma / pathology*
  • Amino Acids / deficiency*
  • Amino Acids / metabolism
  • Apoptosis / physiology
  • Autophagy / physiology*
  • Autophagy-Related Protein 7
  • Cell Line, Tumor
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / pathology*
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Humans
  • Microtubule-Associated Proteins / biosynthesis
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • RNA Interference
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Ubiquitin-Activating Enzymes / genetics
  • Ubiquitin-Activating Enzymes / metabolism

Substances

  • Amino Acids
  • MAP1LC3A protein, human
  • Microtubule-Associated Proteins
  • Recombinant Fusion Proteins
  • green fluorescent protein, Aequorea victoria
  • Green Fluorescent Proteins
  • ATG7 protein, human
  • Autophagy-Related Protein 7
  • Ubiquitin-Activating Enzymes