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dc.contributor.author Boamah, EK
dc.contributor.author Brekman, A
dc.contributor.author Tomasz, M
dc.contributor.author Myeku, N
dc.contributor.author Figueiredo Pereira, M
dc.contributor.author Hunter, S
dc.contributor.author Meyer, J
dc.contributor.author Bhosle, RC
dc.contributor.author Bargonetti, J
dc.date.accessioned 2011-06-21T17:27:12Z
dc.date.issued 2010
dc.identifier.citation Chem Res Toxicol, 2010, 23 (7), pp. 1151 - 1162
dc.identifier.uri http://hdl.handle.net/10161/4114
dc.description.abstract The mitomycin derivative 10-decarbamoyl mitomycin C (DMC) more rapidly activates a p53-independent cell death pathway than mitomycin C (MC). We recently documented that an increased proportion of mitosene1-beta-adduct formation occurs in human cells treated with DMC in comparison to those treated with MC. Here, we compare the cellular and molecular response of human cancer cells treated with MC and DMC. We find the increase in mitosene 1-beta-adduct formation correlates with a condensed nuclear morphology and increased cytotoxicity in human cancer cells with or without p53. DMC caused more DNA damage than MC in the nuclear and mitochondrial genomes. Checkpoint 1 protein (Chk1) was depleted following DMC, and the depletion of Chk1 by DMC was achieved through the ubiquitin proteasome pathway since chemical inhibition of the proteasome protected against Chk1 depletion. Gene silencing of Chk1 by siRNA increased the cytotoxicity of MC. DMC treatment caused a decrease in the level of total ubiquitinated proteins without increasing proteasome activity, suggesting that DMC mediated DNA adducts facilitate signal transduction to a pathway targeting cellular proteins for proteolysis. Thus, the mitosene-1-beta stereoisomeric DNA adducts produced by the DMC signal for a p53-independent mode of cell death correlated with reduced nuclear size, persistent DNA damage, increased ubiquitin proteolysis and reduced Chk1 protein.
dc.format.extent 1151 - 1162
dc.language.iso en_US en_US
dc.relation.ispartof Chem Res Toxicol
dc.subject Apoptosis Cell Line
dc.subject Tumor DNA Adducts/*chemistry DNA Damage Gene Silencing Humans Mitomycin/toxicity Mitomycins/*chemistry/toxicity Proteasome Endopeptidase Complex/*metabolism Protein Kinases/*metabolism RNA Interference RNA
dc.subject Small Interfering/metabolism Tumor Suppressor Protein p53/genetics/*metabolism
dc.title DNA adducts of decarbamoyl mitomycin C efficiently kill cells without wild-type p53 resulting from proteasome-mediated degradation of checkpoint protein 1
dc.title.alternative en_US
dc.type Journal Article
dc.description.version Version of Record en_US
duke.date.pubdate 2010-7-0 en_US
duke.description.endpage 1162 en_US
duke.description.issue 7 en_US
duke.description.startpage 1151 en_US
duke.description.volume 23 en_US
dc.relation.journal Chemical research in toxicology en_US
pubs.issue 7
pubs.organisational-group /Duke
pubs.organisational-group /Duke/Nicholas School of the Environment
pubs.organisational-group /Duke/Nicholas School of the Environment/Environmental Sciences and Policy
pubs.organisational-group /Duke/School of Medicine
pubs.organisational-group /Duke/School of Medicine/Institutes and Centers
pubs.organisational-group /Duke/School of Medicine/Institutes and Centers/Duke Cancer Institute
pubs.publication-status Published
pubs.volume 23

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