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

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 cancer1. 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-ApcMin /J (ApcMin ) 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.

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Figure 1: TRAIL and RAc induce apoptosis in APC-deficient cells.
Figure 2: Downregulation of c-FLIP by APC/β-catenin-mediated activation of c-Myc and modulation of TRAIL receptor expression by RAc contribute to the activation of TRAIL signalling.
Figure 3: Treatment with TRAIL and RAc induces cell death in the polyps, inhibits tumour growth, and promote survival in Apc Min mice.
Figure 4: Effect of TRAIL and RAc on human colon polyps and ISCs.

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Acknowledgements

We thank H. Yang for technical support, R. Lotan for the BW1799 cells, and W. El-Deiry for DR5 expression plasmid; and M. Chambers, J. Yate, L. Ingram, D. Chow and G. Reyes for their involvement in IRB approval and human tissue acquisition. We also thank J. Vykoukal, A. E. Kadala and D. Malone for their help in editing the manuscript. This work was supported by NIH grant AI063063 and Institutional Funds from M. D. Anderson Cancer Center (to X.W.), and in part by Alliance of Cardiovascular Researchers grant 543102 (to E.A.).

Author Contributions X.W. designed and supervised the experiments, and also analysed the data and wrote the paper. X.R. initiated the experiments, and L.Z. performed most of the experiments and participated in designing experiments and analysing data. E.A. designed the mASC experiments and edited and partially wrote the paper. X.B. performed experiments in mASCs. S.H., Z.X. and X.-F.W. helped perform the experiments. P.M.L. provided human tumour samples. M.P.M. provided cell lines.

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Correspondence to Xiangwei Wu.

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Zhang, L., Ren, X., Alt, E. et al. Chemoprevention of colorectal cancer by targeting APC-deficient cells for apoptosis. Nature 464, 1058–1061 (2010). https://doi.org/10.1038/nature08871

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