BCL-XL is crucial for progression through the adenoma-to-carcinoma sequence of colorectal cancer.

Cell Death and Differentiation
Prashanthi RameshJan Paul Medema

Abstract

Evasion of apoptosis is a hallmark of cancer, which is frequently mediated by upregulation of the antiapoptotic BCL-2 family proteins. In colorectal cancer (CRC), previous work has highlighted differential antiapoptotic protein dependencies determined by the stage of the disease. While intestinal stem cells (ISCs) require BCL-2 for adenoma outgrowth and survival during transformation, ISC-specific MCL1 deletion results in disturbed intestinal homeostasis, eventually contributing to tumorigenesis. Colon cancer stem cells (CSCs), however, no longer require BCL-2 and depend mainly on BCL-XL for their survival. We therefore hypothesized that a shift in antiapoptotic protein reliance occurs in ISCs as the disease progresses from normal to adenoma to carcinoma. By targeting antiapoptotic proteins with specific BH3 mimetics in organoid models of CRC progression, we found that BCL-2 is essential only during ISC transformation while MCL1 inhibition did not affect adenoma outgrowth. BCL-XL, on the other hand, was crucial for stem cell survival throughout the adenoma-to-carcinoma sequence. Furthermore, we identified that the limited window of BCL-2 reliance is a result of its downregulation by miR-17-5p, a microRNA that is upregulated upo...Continue Reading

References

Jan 27, 2000·Cell·D Hanahan, R A Weinberg
Jun 10, 2005·Nature·Kathryn A O'DonnellJoshua T Mendell
Aug 1, 2006·Nature Genetics·Michael DewsAndrei Thomas-Tikhonenko
Mar 27, 2007·Cell·Kylie D MasonBenjamin T Kile
May 22, 2008·World Journal of Gastroenterology : WJG·You-Li ZhangYu Fan
Oct 25, 2008·The Journal of Clinical Investigation·Mark S CraggClare L Scott
Dec 9, 2008·Cancer Cell·Daniel J MurphyGerard I Evan
Feb 19, 2010·Nature·Rameen BeroukhimMatthew Meyerson
Apr 27, 2010·Nature Cell Biology·Louis VermeulenJan Paul Medema
Nov 9, 2011·Journal of Surgical Oncology·Ge YuYuan-Lian Wan
Oct 5, 2012·Nucleic Acids Research·Charles E Vejnar, Evgeny M Zdobnov
Jul 13, 2013·Cancer Cell·François VaillantGeoffrey J Lindeman
Apr 1, 2014·Cell Death and Differentiation·S ColakJ P Medema
Sep 2, 2014·Cell Reports·Nathiya MuthalaguDaniel J Murphy
Oct 15, 2014·ACS Medicinal Chemistry Letters·Zhi-Fu TaoAndrew J Souers
Apr 30, 2015·Nature·Jarno DrostHans Clevers
Nov 10, 2015·Stem Cell Reports·Peter JungEduard Batlle
Mar 10, 2016·Nature Communications·Maartje van der HeijdenLouis Vermeulen
May 26, 2016·EMBO Molecular Medicine·Evelyn FesslerJan Paul Medema
Aug 19, 2016·Cell Death & Disease·Anna-Lena ScherrBruno Christian Koehler
Oct 28, 2016·Nature·András KotschyOlivier Geneste
May 18, 2018·Open Biology·Kirsteen J Campbell, Stephen W G Tait
Nov 11, 2018·Methods in Molecular Biology·Prashanthi RameshJan Paul Medema
Nov 20, 2018·Molecular Oncology·Lotteke J Y M SwierJoost Kluiver
Dec 12, 2018·Cancer Cell·Delphine MerinoAndreas Strasser
May 1, 2019·Nature Genetics·Ana C F BolhaqueiroGeert J P L Kops
Jul 25, 2019·Cell Death and Differentiation·Mariana Villalobos-OrtizAnthony Letai
Oct 11, 2019·Science Translational Medicine·Salo N OoftEmile E Voest

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