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DNA damage, induced by either chemical carcinogens or environmental pollutants, plays an important role in the initiation of colorectal cancer. DNA repair processes, however, are involved in both protecting against cancer formation, and also contributing to cancer development, by ensuring genomic integrity and promoting the efficient DNA repair in tumor cells, respectively. Although DNA repair pathways have been well exploited in the treatment of breast and ovarian cancers, the role of DNA repair processes and their therapeutic efficacy in colorectal cancer is yet to be appreciably explored. To understand the role of DNA repair, especially homologous recombination (HR), in chemical carcinogen-induced colorectal cancer growth, we unraveled the role of RAD51AP1 (RAD51-associated protein 1), a protein involved in HR, in genotoxic carcinogen (azoxymethane, AOM)-induced colorectal cancer. Although AOM treatment alone significantly increased RAD51AP1 expression, the combination of AOM and dextran sulfate sodium (DSS) treatment dramatically increased by several folds. RAD51AP1 expression is found in mouse colonic crypt and proliferating cells. RAD51AP1 expression is significantly increased in majority of human colorectal cancer tissues, including BRAF/KRAS mutant colorectal cancer, and associated with reduced treatment response and poor prognosis. Rad51ap1 -deficient mice were protected against AOM/DSS-induced colorectal cancer. These observations were recapitulated in a genetically engineered mouse model of colorectal cancer ( Apc Min /+ ). Furthermore, chemotherapy-resistant colorectal cancer is associated with increased RAD51AP1 expression. This phenomenon is associated with reduced cell proliferation and colorectal cancer stem cell (CRCSC) self-renewal. Overall, our studies provide evidence that RAD51AP1 could be a novel diagnostic marker for colorectal cancer and a potential therapeutic target for colorectal cancer prevention and treatment. IMPLICATIONS: This study provides first in vivo evidence that RAD51AP1 plays a critical role in colorectal cancer growth and drug resistance by regulating CRCSC self-renewal.

Titel:	RAD51AP1 Loss Attenuates Colorectal Cancer Stem Cell Renewal and Sensitizes to Chemotherapy.
Autor/in / Beteiligte Person:	Bridges, AE ; Ramachandran, S ; Tamizhmani, K ; Parwal, U ; Lester, A ; Rajpurohit, P ; Morera, DS ; Hasanali, SL ; Arjunan, P ; Jedeja, RN ; Patel, N ; Martin, PM ; Korkaya, H ; Singh, N ; Manicassamy, S ; Prasad, PD ; Lokeshwar, VB ; Lokeshwar, BL ; Ganapathy, V ; Thangaraju, M
Link:	Full Text Finder (Volltext)
Zeitschrift:	Molecular cancer research : MCR, Jg. 19 (2021-09-01), Heft 9, S. 1486-1497
Veröffentlichung:	Philadelphia, PA : American Association for Cancer Research, c2002-, 2021
Medientyp:	academicJournal
ISSN:	1557-3125 (electronic)
DOI:	10.1158/1541-7786.MCR-20-0780
Schlagwort:	Animals Antimetabolites, Antineoplastic pharmacology Apoptosis Case-Control Studies Cell Proliferation Colorectal Neoplasms metabolism Colorectal Neoplasms pathology DNA-Binding Proteins genetics Humans Mice Mice, Inbred C57BL Mice, Knockout Neoplastic Stem Cells metabolism Neoplastic Stem Cells pathology Prognosis RNA-Binding Proteins genetics Survival Rate Tumor Cells, Cultured Cell Self Renewal Colorectal Neoplasms drug therapy DNA-Binding Proteins metabolism DNA-Binding Proteins physiology Drug Resistance, Neoplasm Fluorouracil pharmacology Neoplastic Stem Cells drug effects RNA-Binding Proteins metabolism RNA-Binding Proteins physiology
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Language: English [Mol Cancer Res] 2021 Sep; Vol. 19 (9), pp. 1486-1497. <i>Date of Electronic Publication: </i>2021 Jun 07. MeSH Terms: Cell Self Renewal* ; Drug Resistance, Neoplasm* ; Colorectal Neoplasms / drug therapy ; DNA-Binding Proteins / metabolism ; DNA-Binding Proteins / physiology ; Fluorouracil / pharmacology ; Neoplastic Stem Cells / drug effects ; RNA-Binding Proteins / metabolism ; RNA-Binding Proteins / *physiology ; Animals ; Antimetabolites, Antineoplastic / pharmacology ; Apoptosis ; Case-Control Studies ; Cell Proliferation ; Colorectal Neoplasms / metabolism ; Colorectal Neoplasms / pathology ; DNA-Binding Proteins / genetics ; Humans ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Neoplastic Stem Cells / metabolism ; Neoplastic Stem Cells / pathology ; Prognosis ; RNA-Binding Proteins / genetics ; Survival Rate ; Tumor Cells, Cultured References: Asian Pac J Cancer Prev. 2015;16(9):3667-71. (PMID: 25987019) ; Biochim Biophys Acta. 2005 Jun 30;1741(1-2):215-23. (PMID: 15905073) ; Ann Oncol. 2018 Apr 1;29(4):1016-1022. (PMID: 29562308) ; Cancer Res. 2016 Jun 1;76(11):3224-35. (PMID: 27197203) ; Oncogene. 2013 Jul 25;32(30):3500-9. (PMID: 22945654) ; Stem Cells. 2015 Aug;33(8):2381-90. (PMID: 25821200) ; Cancer Res. 2009 Apr 1;69(7):2826-32. (PMID: 19276343) ; Proc Natl Acad Sci U S A. 2011 Mar 1;108(9):3560-5. (PMID: 21307306) ; PLoS One. 2015 Mar 09;10(3):e0118792. (PMID: 25751518) ; Cell Res. 2008 Jan;18(1):134-47. (PMID: 18157161) ; Nat Rev Mol Cell Biol. 2010 Mar;11(3):196-207. (PMID: 20177395) ; Cancer Res. 2020 Sep 15;80(18):3855-3866. (PMID: 32665355) ; Nature. 2006 Jul 13;442(7099):153-8. (PMID: 16838012) ; Thorac Cancer. 2019 Sep;10(9):1748-1763. (PMID: 31317661) ; Nat Rev Clin Oncol. 2015 Oct;12(10):607-19. (PMID: 26215044) ; Science. 1992 May 1;256(5057):668-70. (PMID: 1350108) ; Mol Cell Biol. 2013 Oct;33(19):3920-35. (PMID: 23918800) ; Stem Cells. 2009 May;27(5):993-1005. (PMID: 19415763) ; Cancer Res. 2011 Nov 1;71(21):6654-64. (PMID: 21920899) ; Nat Rev Cancer. 2005 Apr;5(4):275-84. (PMID: 15803154) ; DNA Repair (Amst). 2014 Dec;24:87-97. (PMID: 25288561) ; Nature. 2007 Jan 4;445(7123):111-5. (PMID: 17122771) ; Nat Rev Cancer. 2012 Sep;12(9):587-98. (PMID: 22918414) ; Nat Cell Biol. 2010 May;12(5):468-76. (PMID: 20418870) ; CA Cancer J Clin. 2018 Jan;68(1):31-54. (PMID: 29160902) ; Nat Rev Cancer. 2014 Jul;14(7):468-80. (PMID: 24920463) ; Mol Cell. 2007 Nov 9;28(3):468-81. (PMID: 17996710) ; Clin Cancer Res. 2010 Jun 15;16(12):3113-20. (PMID: 20530701) ; Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):3070-4. (PMID: 1348364) ; Nat Rev Cancer. 2008 Oct;8(10):755-68. (PMID: 18784658) ; Nat Rev Mol Cell Biol. 2008 Apr;9(4):297-308. (PMID: 18285803) ; Biol Direct. 2016 Oct 12;11(1):51. (PMID: 27733173) ; Nat Rev Cancer. 2008 Mar;8(3):193-204. (PMID: 18256616) ; Cancer Res. 2006 Dec 15;66(24):11560-4. (PMID: 17178845) ; Medicine (Baltimore). 2019 Aug;98(35):e16941. (PMID: 31464932) ; Nat Commun. 2015 Apr 24;6:6910. (PMID: 25908435) ; World J Gastroenterol. 2014 Aug 7;20(29):9872-81. (PMID: 25110418) ; J Natl Cancer Inst. 2017 Sep 1;109(9):. (PMID: 28376154) ; Cancer Res. 2000 Aug 1;60(15):4231-7. (PMID: 10945635) ; Nature. 2001 May 17;411(6835):366-74. (PMID: 11357144) ; Cancer Sci. 2003 Nov;94(11):965-73. (PMID: 14611673) ; Clin Cancer Res. 2008 Mar 1;14(5):1333-9. (PMID: 18316552) ; Stem Cells Int. 2017;2017:2925869. (PMID: 28356914) ; Cell. 2013 Jan 17;152(1-2):25-38. (PMID: 23273993) ; CA Cancer J Clin. 2020 May;70(3):145-164. (PMID: 32133645) ; Cancer Biol Ther. 2016;17(1):1-10. (PMID: 26618281) ; Science. 2000 Mar 17;287(5460):2017-9. (PMID: 10720328) ; Cell. 1992 May 1;69(3):439-56. (PMID: 1581960) ; Genes Chromosomes Cancer. 2005 Jul;43(3):227-38. (PMID: 15846790) Grant Information: R01 DK123360 United States DK NIDDK NIH HHS Substance Nomenclature: 0 (Antimetabolites, Antineoplastic) ; 0 (DNA-Binding Proteins) ; 0 (RAD51AP1 protein, human) ; 0 (RNA-Binding Proteins) ; 0 (Rad51ap1 protein, mouse) ; U3P01618RT (Fluorouracil) Entry Date(s): Date Created: 20210608 Date Completed: 20220207 Latest Revision: 20220302 Update Code: 20240513 PubMed Central ID: PMC8612176

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RAD51AP1 Loss Attenuates Colorectal Cancer Stem Cell Renewal and Sensitizes to Chemotherapy.