Linked Life Data

12140766

Source:http://linkedlifedata.com/resource/pubmed/id/12140766

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
33
pubmed:dateCreated
2002-7-25
pubmed:abstractText
We report here that expression of proteinase 3 (PR3), a serine protease, is down-regulated in the HL60/ADR multidrug resistant variant of the human myelogenous leukemia cell line HL-60, and that down-regulation of PR3 is associated with doxorubicin (DOX) resistance in these cells. To determine whether PR3 is involved in DOX-induced apoptosis in HL-60 cells, and whether its loss causes resistance to DOX, we inhibited PR3 expression by an anti-sense PR3 oligodeoxynucleotide and showed that inhibition of PR3 expression results in a significant reduction in DOX-induced DNA fragmentation and increased resistance to DOX-induced apoptosis. Our results revealed that PR3-mediated DOX-induced apoptosis in HL-60 cells is independent of the loss of mitochondrial membrane potential (deltapsi(m)) and activation of the caspase-8 and -9 pathways. Moreover, while PR3 is involved in the cleavage of caspase-3, PR3-mediated DOX-induced DNA fragmentation and apoptosis were not prevented by a specific inhibitor of caspase-3. These data suggest that activation of caspase-3 alone is not sufficient to trigger PR3-mediated DOX-induced apoptosis. Treatment with an anti-PR3 oligomer significantly decreased reactive oxygen species (ROS) generation in cells treated with low concentrations of DOX, revealing a role for PR3 in enhancing production of DOX-induced ROS. Moreover, DOX-induced apoptosis at 0.001-0.01 microM was only inhibited in HL-60 cells pre-treated with the antioxidant N-acetyl-cysteine in the absence of anti-PR3, revealing that DOX-induced apoptosis in these cells is PR3- and ROS-dependent. Our results show that PR3 is involved in DOX-induced ROS-dependent apoptosis and that its loss is associated with resistance to DOX in HL-60 cells.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Aug
pubmed:issn
0950-9232
pubmed:author
pubmed:issnType
Print
pubmed:day
1
pubmed:volume
21
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
5160-74
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed-meshheading:12140766-Apoptosis, pubmed-meshheading:12140766-Caspases, pubmed-meshheading:12140766-DNA Fragmentation, pubmed-meshheading:12140766-Down-Regulation, pubmed-meshheading:12140766-Doxorubicin, pubmed-meshheading:12140766-Drug Resistance, Neoplasm, pubmed-meshheading:12140766-Flow Cytometry, pubmed-meshheading:12140766-Gene Expression Regulation, Neoplastic, pubmed-meshheading:12140766-HL-60 Cells, pubmed-meshheading:12140766-Humans, pubmed-meshheading:12140766-In Situ Nick-End Labeling, pubmed-meshheading:12140766-Inhibitory Concentration 50, pubmed-meshheading:12140766-Intracellular Membranes, pubmed-meshheading:12140766-Membrane Potentials, pubmed-meshheading:12140766-Mitochondria, pubmed-meshheading:12140766-Myeloblastin, pubmed-meshheading:12140766-Oligonucleotides, Antisense, pubmed-meshheading:12140766-RNA, Messenger, pubmed-meshheading:12140766-Reactive Oxygen Species, pubmed-meshheading:12140766-Serine Endopeptidases
pubmed:year
2002
pubmed:articleTitle
Proteinase-3, a serine protease which mediates doxorubicin-induced apoptosis in the HL-60 leukemia cell line, is downregulated in its doxorubicin-resistant variant.
pubmed:affiliation
Department of Pharmacology and Toxicology, Indiana University, 1044 West Walnut R4-119, Indianapolis, Indiana, IN 46202, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't