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

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Title: Chemoprevention of colorectal cancer by targeting APC-deficient cells for apoptosis.
Authors: Ling Zhang, Xiaoyang Ren, Alt, Eckhard, Xiaowen Bai, Shaoyi Huang, Zhengming Xu, Lynch, Patrick M., Moyer, Mary P., Xian-Feng Wen, Xiangwei Wu
Source: Nature. 4/15/2010, Vol. 464 Issue 7291, p1058-1061. 4p. 1 Diagram, 3 Graphs.
Subjects: Colon cancer, Chemoprevention, Apoptosis, Carcinogenesis, Toxicity testing, Tumors
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-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. [ABSTRACT FROM AUTHOR]
Copyright of Nature is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Psychology and Behavioral Sciences Collection
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  Data: Chemoprevention of colorectal cancer by targeting APC-deficient cells for apoptosis.
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  Data: <searchLink fieldCode="AR" term="%22Ling+Zhang%22">Ling Zhang</searchLink><br /><searchLink fieldCode="AR" term="%22Xiaoyang+Ren%22">Xiaoyang Ren</searchLink><br /><searchLink fieldCode="AR" term="%22Alt%2C+Eckhard%22">Alt, Eckhard</searchLink><br /><searchLink fieldCode="AR" term="%22Xiaowen+Bai%22">Xiaowen Bai</searchLink><br /><searchLink fieldCode="AR" term="%22Shaoyi+Huang%22">Shaoyi Huang</searchLink><br /><searchLink fieldCode="AR" term="%22Zhengming+Xu%22">Zhengming Xu</searchLink><br /><searchLink fieldCode="AR" term="%22Lynch%2C+Patrick+M%2E%22">Lynch, Patrick M.</searchLink><br /><searchLink fieldCode="AR" term="%22Moyer%2C+Mary+P%2E%22">Moyer, Mary P.</searchLink><br /><searchLink fieldCode="AR" term="%22Xian-Feng+Wen%22">Xian-Feng Wen</searchLink><br /><searchLink fieldCode="AR" term="%22Xiangwei+Wu%22">Xiangwei Wu</searchLink>
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  Data: <searchLink fieldCode="JN" term="%22Nature%22">Nature</searchLink>. 4/15/2010, Vol. 464 Issue 7291, p1058-1061. 4p. 1 Diagram, 3 Graphs.
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  Data: <searchLink fieldCode="DE" term="%22Colon+cancer%22">Colon cancer</searchLink><br /><searchLink fieldCode="DE" term="%22Chemoprevention%22">Chemoprevention</searchLink><br /><searchLink fieldCode="DE" term="%22Apoptosis%22">Apoptosis</searchLink><br /><searchLink fieldCode="DE" term="%22Carcinogenesis%22">Carcinogenesis</searchLink><br /><searchLink fieldCode="DE" term="%22Toxicity+testing%22">Toxicity testing</searchLink><br /><searchLink fieldCode="DE" term="%22Tumors%22">Tumors</searchLink>
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  Data: 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-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. [ABSTRACT FROM AUTHOR]
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  Data: <i>Copyright of Nature is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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              Text: 4/15/2010
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