Abstract:
:The retinoid 4-oxo-N-(4-hydroxyphenyl)retinamide (4-oxo-4-HPR), a metabolite of fenretinide (4-HPR) present in plasma of 4-HPR-treated patients, is very effective in inducing growth inhibition and apoptosis in several cancer cell lines. 4-Oxo-4-HPR and 4-HPR have different mechanisms of action because 4-oxo-4-HPR, unlike 4-HPR, causes marked cell accumulation in G2-M phase. Here, we investigated the molecular events involving 4-oxo-4-HPR-induced cell cycle perturbation in ovarian (A2780 and IGROV-1) and breast (T47D, estrogen receptor+ and BT-20, estrogen receptor-) cancer cells. 4-Oxo-4-HPR induced a delay of mitosis (with mitotic index increasing 5- to 6-fold in all cell lines) without progression beyond the anaphase, as shown by cyclin B1 expression. 4-Oxo-4-HPR induced multipolar spindle formation and phosphorylation of BUBR1, resulting in activation of the spindle checkpoint. Multipolar spindles were not due to impairment of pole-focusing process, loss of centrosome integrity, or modulation of the expression levels of molecules associated with spindle aberrations (Kif 1C, Kif 2A, Eg5, Tara, tankyrase-1, centractin, and TOGp). We show here that 4-oxo-4-HPR targets microtubules because, in treated cells, it interfered with the reassembly of cold-depolymerized spindle microtubules and decreased the polymerized tubulin fraction. In cell-free assays, 4-oxo-4-HPR inhibited tubulin polymerization (50% inhibition of microtubule assembly at 5.9 micromol/L), suggesting a direct molecular interaction with tubulin. In conclusion, by showing that 4-oxo-4-HPR causes mitotic arrest through antimicrotubule activities, we delineate a new molecular mechanism for a retinoid.
journal_name
Mol Cancer Therjournal_title
Molecular cancer therapeuticsauthors
Appierto V,Tiberio P,Cavadini E,Casalini P,Cappelletti G,Formelli Fdoi
10.1158/1535-7163.MCT-09-0798subject
Has Abstractpub_date
2009-12-01 00:00:00pages
3360-8issue
12eissn
1535-7163issn
1538-8514pii
1535-7163.MCT-09-0798journal_volume
8pub_type
杂志文章abstract::Prostate-specific membrane antigen (PSMA) is a protein up-regulated in the vast majority of prostate cancers. Antibodies to PSMA have proved highly specific for prostate cancer cells, and the therapeutic potential of such antibodies is currently being assessed in clinical trials. We have previously shown that PSMA at ...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-06-0253
更新日期:2006-10-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-17-0341
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-08-1056
更新日期:2009-05-01 00:00:00
abstract::Aberrant overexpression of antiapoptotic members of the Bcl-2 protein family, including Bcl-2 and Bcl-X(L), contributes to malignant transformation and subsequent resistance to traditional chemotherapeutics. Thus, these proteins represent attractive targets for novel anticancer agents. The small molecule, gossypol, wa...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-09-0013
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pub_type: 杂志文章
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更新日期:2017-07-01 00:00:00
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pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-14-0710
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-04-0328
更新日期:2005-09-01 00:00:00
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pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-14-0354
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-16-0005
更新日期:2016-06-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-04-0209
更新日期:2005-03-01 00:00:00
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pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-11-0424
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pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-16-0337
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-17-0981
更新日期:2018-03-01 00:00:00
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doi:10.1158/1535-7163.MCT-06-0111
更新日期:2006-08-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-09-0380
更新日期:2009-09-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-12-0342
更新日期:2012-10-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-14-0248
更新日期:2014-11-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-16-0243
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pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-06-0581
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:
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pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-17-0298
更新日期:2018-09-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-08-0015
更新日期:2008-08-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-15-0985
更新日期:2016-06-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-10-0581
更新日期:2011-01-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-06-0002
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-05-0190
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-06-0315
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