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rdf:type |
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lifeskim:mentions |
umls-concept:C0007600,
umls-concept:C0013081,
umls-concept:C0021760,
umls-concept:C0025646,
umls-concept:C0086418,
umls-concept:C0127400,
umls-concept:C0205263,
umls-concept:C0242643,
umls-concept:C0538927,
umls-concept:C0596138,
umls-concept:C1417123,
umls-concept:C1442521,
umls-concept:C1518174,
umls-concept:C2239176
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pubmed:issue |
1
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pubmed:dateCreated |
2009-5-18
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pubmed:abstractText |
Many tumors are resistant to drug-induced cell-cycle arrest and apoptosis. We have reported that apoptosis can be restored in human multidrug-resistant (MDR) hepatocellular carcinoma cell lines by celecoxib. Here we show that P-glycoprotein (P-gp) mediates cell-cycle arrest and autophagy induced by celecoxib in human MDR overexpressing hepatocellular carcinoma cell line by down-regulation of the HGF/MET autocrine loop and Bcl-2 expression. Exposure of cells to a low concentration of celecoxib down-regulated the expression of mTOR and caused G1 arrest and autophagy, while higher concentration triggered apoptosis. Cell growth inhibition and autophagy were associated with up-regulation of the expression of TGFbeta1, p16(INK4b), p21(Cip1) and p27(Kip1) and down-regulation of cyclin D1, cyclin E, pRb and E2F. The role of P-glycoprotein expression in resistance of MDR cell clone to cell-cycle arrest, autophagy and apoptosis was shown in cells transfected with MDR1 small interfering RNA. These findings demonstrate that the constitutive expression of P-gp is involved in the HGF/MET autocrine loop that leads to increased expression of Bcl-2 and mTor, inhibition of eIF2alpha expression, resistance to autophagy/apoptosis and progression in the cell-cycle. Since mTor inhibitors have been proposed in treatment of "drug resistant" cancer, these data may help explain the reversing effect of mTor inhibitors.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Cyclin D1,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclin-Dependent Kinase Inhibitor...,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclin-Dependent Kinase Inhibitor...,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclooxygenase Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Glyceraldehyde 3-Phosphate...,
http://linkedlifedata.com/resource/pubmed/chemical/Hepatocyte Growth Factor,
http://linkedlifedata.com/resource/pubmed/chemical/P-Glycoprotein,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-bcl-2,
http://linkedlifedata.com/resource/pubmed/chemical/Pyrazoles,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Neoplasm,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Small Interfering,
http://linkedlifedata.com/resource/pubmed/chemical/Sulfonamides,
http://linkedlifedata.com/resource/pubmed/chemical/celecoxib
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pubmed:status |
MEDLINE
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pubmed:month |
Jul
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pubmed:issn |
1873-2968
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pubmed:author |
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pubmed:issnType |
Electronic
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pubmed:day |
1
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pubmed:volume |
78
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
21-32
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pubmed:meshHeading |
pubmed-meshheading:19447220-Apoptosis,
pubmed-meshheading:19447220-Carcinoma, Hepatocellular,
pubmed-meshheading:19447220-Cell Cycle,
pubmed-meshheading:19447220-Cell Division,
pubmed-meshheading:19447220-Cell Line, Tumor,
pubmed-meshheading:19447220-Cyclin D1,
pubmed-meshheading:19447220-Cyclin-Dependent Kinase Inhibitor p16,
pubmed-meshheading:19447220-Cyclin-Dependent Kinase Inhibitor p27,
pubmed-meshheading:19447220-Cyclooxygenase Inhibitors,
pubmed-meshheading:19447220-Drug Resistance, Multiple,
pubmed-meshheading:19447220-G1 Phase,
pubmed-meshheading:19447220-Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+),
pubmed-meshheading:19447220-Hepatocyte Growth Factor,
pubmed-meshheading:19447220-Humans,
pubmed-meshheading:19447220-Liver Neoplasms,
pubmed-meshheading:19447220-P-Glycoprotein,
pubmed-meshheading:19447220-Proto-Oncogene Proteins c-bcl-2,
pubmed-meshheading:19447220-Pyrazoles,
pubmed-meshheading:19447220-RNA, Neoplasm,
pubmed-meshheading:19447220-RNA, Small Interfering,
pubmed-meshheading:19447220-Sulfonamides
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pubmed:year |
2009
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pubmed:articleTitle |
Down-regulation of the HGF/MET autocrine loop induced by celecoxib and mediated by P-gp in MDR-positive human hepatocellular carcinoma cell line.
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pubmed:affiliation |
2nd Medical Oncology of Azienda Ospedaliero-Universitaria Careggi, University of Florence, Istituto Toscano Tumori, Florence, Italy. mazzanti-lab@dmi.unifi.it
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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