Linked Life Data

21300766

Source:http://linkedlifedata.com/resource/pubmed/id/21300766

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
7
pubmed:dateCreated
2011-4-4
pubmed:databankReference
pubmed:abstractText
Microsatellite instability (MSI) is displayed by approximately 15% of colorectal cancers (CRC). Defective DNA mismatch repair generates mutations at repetitive DNA sequences such as those located in the double strand break (DSB) repair gene MRE11. We assessed the mutational status of MRE11 in a panel of 17 CRC cell lines and 46 primary tumors and found a strong correlation with MSI status in both cell lines and tumors. Therefore, we hypothesized that deficiency in MRE11 may sensitize CRC cells to poly(ADP-ribose) polymerase (PARP-1) inhibition based on the concept of synthetic lethality. We further assessed the activity of the PARP-1 inhibitor, ABT-888, in CRC cell lines and observed preferential cytotoxicity in those MSI cell lines harboring mutations in MRE11 compared with both wild-type cell lines and microsatellite stable (MSS) cell lines. A significant correlation between MRE11 expression levels and cytotoxicity to ABT-888 at 10 ?M was observed (R² = 0.915, P < 0.001). Using two experimental approaches, including short hairpin RNA knocking down MRE11 in the wild-type and MSS cell line SW-480 and a second cell line model transfected with mutant MRE11, we experimentally tried to confirm the role of MRE11 in conferring sensitivity to PARP-1 inhibition. Both models led to changes in proliferation in response to ABT-888 at different concentrations, and a drug-response effect was not observed, suggesting a possible contribution of additional genes. We conclude that MSI colorectal tumors deficient in DSB repair secondary to mutation in MRE11 show a higher sensitivity to PARP-1 inhibition. Further clinical investigation of PARP-1 inhibitors is warranted in MSI CRCs.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/2-((R)-2-methylpyrrolidin-2-yl)-1H-b..., http://linkedlifedata.com/resource/pubmed/chemical/Benzimidazoles, http://linkedlifedata.com/resource/pubmed/chemical/DNA Repair Enzymes, http://linkedlifedata.com/resource/pubmed/chemical/DNA-Binding Proteins, http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors, http://linkedlifedata.com/resource/pubmed/chemical/MRE11A protein, human, http://linkedlifedata.com/resource/pubmed/chemical/PARP1 protein, human, http://linkedlifedata.com/resource/pubmed/chemical/Poly(ADP-ribose) Polymerases, http://linkedlifedata.com/resource/pubmed/chemical/RAD51 protein, human, http://linkedlifedata.com/resource/pubmed/chemical/Rad50 protein, human, http://linkedlifedata.com/resource/pubmed/chemical/Rad51 Recombinase
pubmed:status
MEDLINE
pubmed:month
Apr
pubmed:issn
1538-7445
pubmed:author
pubmed:issnType
Electronic
pubmed:day
1
pubmed:volume
71
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
2632-42
pubmed:dateRevised
2011-9-22
pubmed:meshHeading
pubmed:year
2011
pubmed:articleTitle
MRE11 deficiency increases sensitivity to poly(ADP-ribose) polymerase inhibition in microsatellite unstable colorectal cancers.
pubmed:affiliation
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA.
pubmed:publicationType
Journal Article, Research Support, N.I.H., Extramural