Chemoprevention of Colorectal Cancer by Targeting APC-deficient Cells for Apoptosis

Nature. 2010 Apr 15;464(7291):1058-61. doi: 10.1038/nature08871. Epub 2010 Mar 28.

Abstract

Cancer chemoprevention uses natural, synthetic, or biological substances to reverse, suppress, or prevent either the initial phase of carcinogenesis or the progression of neoplastic cells to cancer. It holds promise for overcoming problems associated with the treatment of late-stage cancers. However, the broad application of chemoprevention is compromised at present by limited effectiveness and potential toxicity. To overcome these challenges, here we developed a new chemoprevention approach that specifically targets premalignant tumour cells for apoptosis. We show that a deficiency in the adenomatous polyposis coli (APC) gene and subsequent activation of beta-catenin lead to the repression of cellular caspase-8 inhibitor c-FLIP (also known as CFLAR) expression through activation of c-Myc, and that all-trans-retinyl acetate (RAc) independently upregulates tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptors and suppresses decoy receptors. Thus, the combination of TRAIL and RAc induces apoptosis in APC-deficient premalignant cells without affecting normal cells in vitro. In addition, we show that short-term and non-continuous TRAIL and RAc treatment induce apoptosis specifically in intestinal polyps, strongly inhibit tumour growth, and prolong survival in multiple intestinal neoplasms C57BL/6J-Apc(Min)/J (Apc(Min)) mice. With our approach, we further demonstrate that TRAIL and RAc induce significant cell death in human colon polyps, providing a potentially selective approach for colorectal cancer chemoprevention by targeting APC-deficient cells for apoptosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenomatous Polyposis Coli Protein / deficiency*
  • Adenomatous Polyposis Coli Protein / genetics
  • Animals
  • Apoptosis / drug effects*
  • CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism
  • Cell Proliferation / drug effects
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology*
  • Colorectal Neoplasms / prevention & control*
  • Diterpenes
  • Gene Expression Regulation / drug effects
  • Genes, APC
  • Humans
  • Intestinal Polyps / drug therapy
  • Intestinal Polyps / pathology
  • Mice
  • Mice, Inbred C57BL
  • Precancerous Conditions / drug therapy
  • Precancerous Conditions / genetics
  • Precancerous Conditions / metabolism
  • Precancerous Conditions / pathology
  • Proto-Oncogene Proteins c-myc / metabolism
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism
  • Signal Transduction / drug effects
  • Survival Rate
  • TNF-Related Apoptosis-Inducing Ligand / administration & dosage
  • TNF-Related Apoptosis-Inducing Ligand / pharmacology
  • TNF-Related Apoptosis-Inducing Ligand / therapeutic use
  • Time Factors
  • Vitamin A / administration & dosage
  • Vitamin A / analogs & derivatives*
  • Vitamin A / pharmacology
  • Vitamin A / therapeutic use
  • beta Catenin / metabolism

Substances

  • Adenomatous Polyposis Coli Protein
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Cflar protein, mouse
  • Diterpenes
  • Proto-Oncogene Proteins c-myc
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • beta Catenin
  • Vitamin A
  • retinol acetate