Faculty Collaboration Database

Chemoprevention of colorectal cancer by targeting APC-deficient cells for apoptosis. Nature 2010 Apr 15;464(7291):1058-61

Date

03/30/2010

Pubmed ID

20348907

Pubmed Central ID

PMC3425353

DOI

10.1038/nature08871

Scopus ID

2-s2.0-77951134107 (requires institutional sign-in at Scopus site)   124 Citations

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.

Author List

Zhang L, Ren X, Alt E, Bai X, Huang S, Xu Z, Lynch PM, Moyer MP, Wen XF, Wu X

Author

Xiaowen Bai PhD Associate Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adenomatous Polyposis Coli Protein
Animals
Apoptosis
CASP8 and FADD-Like Apoptosis Regulating Protein
Cell Proliferation
Colorectal Neoplasms
Diterpenes
Gene Expression Regulation
Genes, APC
Humans
Intestinal Polyps
Mice
Mice, Inbred C57BL
Precancerous Conditions
Proto-Oncogene Proteins c-myc
Receptors, TNF-Related Apoptosis-Inducing Ligand
Signal Transduction
Survival Rate
TNF-Related Apoptosis-Inducing Ligand
Time Factors
Vitamin A
beta Catenin