Chemoprevention of colorectal cancer by targeting APC-deficient cells for apoptosis

Ling Zhang, Xiaoyang Ren, Eckhard Alt, Xiaowen Bai, Shaoyi Huang, Zhengming Xu, Patrick M. Lynch, Mary P. Moyer, Xian Feng Wen, Xiangwei Wu

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125 Scopus 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 Β-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.

Original languageEnglish (US)
Pages (from-to)1058-1061
Number of pages4
JournalNature
Volume464
Issue number7291
DOIs
StatePublished - Apr 15 2010
Externally publishedYes

ASJC Scopus subject areas

  • General

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