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Experimental and Molecular Therapeutics

Abstract 2115: A chemicogenetic interrogation of colorectal cancer identifies a shared chemical vulnerability in Wnt signaling and telomere length maintenance.

Ozlem Kulak, Brody Holohan, Xiaofeng Wu and Lawrence Lum
Ozlem Kulak
UTSW Medical Center, Dallas, TX.
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Brody Holohan
UTSW Medical Center, Dallas, TX.
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Xiaofeng Wu
UTSW Medical Center, Dallas, TX.
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Lawrence Lum
UTSW Medical Center, Dallas, TX.
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DOI: 10.1158/1538-7445.AM2013-2115 Published April 2013
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Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC

Abstract

Despite the general acceptance that loss of the APC tumor suppressor is the predominant cancer-initiating event in colorectal cancer (CRC), a therapeutic strategy premised upon disabling deviant gene transcription associated with this phenomenon currently does not exist. Chemical antagonism of the poly-ADP ribosylase enzymes Tankyrase 1 and 2 (Tnks1&2) results in the destruction of the transcriptional co-activator β-catenin by promoting the stability of a β-catenin destruction complex. We have evaluated the consequences of disrupting β-catenin activity on the CRC signaling network using faithful reporters of the most frequently corrupted cellular processes (Wnt/β-catenin, p53, and Kras signaling), and a portfolio of Tnks inhibitors identified from a chemical library screen. In addition to inducing loss of β-catenin activity, the exposure of cells to Tnks inhibitors resulted in increased p53 activity. We demonstrated that this unexpected cellular response is due to loss of Tnks ability to regulate the shelterin complex that protects the telomeric sequences found at the ends of chromosomes. Long term culturing of cancerous cells with Tnks inhibitors resulted in telomere shortening and cellular senescence. Our findings reveal a single agent strategy for targeting two cellular processes that support the renewal of cancer initiating cells - Wnt signaling and telomere length maintenance.

Citation Format: Ozlem Kulak, Brody Holohan, Xiaofeng Wu, Lawrence Lum. A chemicogenetic interrogation of colorectal cancer identifies a shared chemical vulnerability in Wnt signaling and telomere length maintenance. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2115. doi:10.1158/1538-7445.AM2013-2115

  • ©2013 American Association for Cancer Research
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Cancer Research: 73 (8 Supplement)
April 2013
Volume 73, Issue 8 Supplement
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Abstract 2115: A chemicogenetic interrogation of colorectal cancer identifies a shared chemical vulnerability in Wnt signaling and telomere length maintenance.
Ozlem Kulak, Brody Holohan, Xiaofeng Wu and Lawrence Lum
Cancer Res April 15 2013 (73) (8 Supplement) 2115; DOI: 10.1158/1538-7445.AM2013-2115

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Abstract 2115: A chemicogenetic interrogation of colorectal cancer identifies a shared chemical vulnerability in Wnt signaling and telomere length maintenance.
Ozlem Kulak, Brody Holohan, Xiaofeng Wu and Lawrence Lum
Cancer Res April 15 2013 (73) (8 Supplement) 2115; DOI: 10.1158/1538-7445.AM2013-2115
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Cancer Research Online ISSN: 1538-7445
Cancer Research Print ISSN: 0008-5472
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