| Repression of cyclin D1 as a target for germ cell tumors. | |
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MedLine Citation:
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PMID: 17203214 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Metastatic germ cell tumors (GCT) are curable, however GCTs refractory to cisplatin-based chemotherapy have a poor prognosis. This study explores D-type cyclins as molecular targets in GCTs because all-trans-retinoic acid (RA)-mediated differentiation of the human embryonal carcinoma (EC) cell line NT2/D1 is associated with G1 cell cycle arrest and proteasomal degradation of cyclin D1. RA effects on D-type cyclins are compared in human EC cells that are RA sensitive or dually RA and cisplatin resistant (NT2/D1-R1) and in clinical GCTs that have both EC and mature teratoma components. Notably, GCT differentiation was associated with reduced cyclin D1 but increased cyclin D3 expression. RA was shown here to repress cyclin D1 through a transcriptional mechanism in addition to causing its degradation. The siRNA-mediated repression of individual cyclin D species resulted in growth inhibition in both RA sensitive and resistant EC cells. Only repression of cyclin D1 occurred in vitro and when clinical GCTs mature, implicating cyclin D1 as a molecular therapeutic target. To confirm this, the EGFR-tyrosine kinase inhibitor, Erlotinib, was used to repress cyclin D1. This inhibited proliferation in RA and cisplatin sensitive and resistant EC cells. Taken together, these findings implicate cyclin D1 targeting agents for the treatment of GCTs. |
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Authors:
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Sarah J Freemantle; Angelina V Vaseva; Katherine E Ewings; Thomas Bee; Katey A Krizan; Mark R Kelley; Eyas M Hattab; Vincent A Memoli; Candice C Black; Michael J Spinella; Ethan Dmitrovsky |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: International journal of oncology Volume: 30 ISSN: 1019-6439 ISO Abbreviation: Int. J. Oncol. Publication Date: 2007 Feb |
Date Detail:
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Created Date: 2007-01-04 Completed Date: 2007-04-09 Revised Date: 2007-12-03 |
Medline Journal Info:
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Nlm Unique ID: 9306042 Medline TA: Int J Oncol Country: Greece |
Other Details:
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Languages: eng Pagination: 333-40 Citation Subset: IM |
Affiliation:
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Department of Pharmacology and Toxicology, Dartmouth Medical School, HB 7650, Hanover, NH 03755, USA. sarah.freemantle@dartmouth.edu |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Antineoplastic Agents
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pharmacology* Cell Differentiation Cyclin D1 / antagonists & inhibitors*, metabolism* DNA Fragmentation Enzyme Inhibitors / pharmacology Gene Expression Regulation, Neoplastic* Humans Neoplasms, Germ Cell and Embryonal / drug therapy*, metabolism*, pathology Quinazolines / pharmacology RNA, Heterogeneous Nuclear / metabolism RNA, Small Interfering / metabolism Receptors, Retinoic Acid / metabolism Time Factors Tretinoin / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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CA087546/CA/NCI NIH HHS; CA094025/CA/NCI NIH HHS; CA104312/CA/NCI NIH HHS; CA106298/CA/NCI NIH HHS; CA111422/CA/NCI NIH HHS; ES03456/ES/NIEHS NIH HHS; ES05865/ES/NIEHS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents; 0/Enzyme Inhibitors; 0/Quinazolines; 0/RNA, Heterogeneous Nuclear; 0/RNA, Small Interfering; 0/Receptors, Retinoic Acid; 0/erlotinib; 136601-57-5/Cyclin D1; 302-79-4/Tretinoin |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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