| Inhibition of Cot1/Tlp2 oncogene in AML cells reduces ERK5 activation and up-regulates p27Kip1 concomitant with enhancement of differentiation and cell cycle arrest induced by silibinin and 1,25-dihydroxyvitamin D(3). | |
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MedLine Citation:
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PMID: 21084834 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Acute myelogenous leukemia (AML) is a disease characterized by dysregulated cell proliferation associated with impaired cell differentiation, and current treatment regimens rarely save the patient. Thus, new mechanism-based approaches are needed to improve prognosis of this disease. We have investigated in preclinical studies the potential anti-leukemia use of the plant-derived polyphenol Silibinin (SIL) in combination with 1,25-dihydroxyvitamin D3 (1,25D). Although most of the leukemic blasts ex vivo responded by differentiation to treatment with this combination, the reasons for the absence of SIL-1,25D synergy in some cases were unclear. Here we report that failure of SIL to enhance the action of 1,25D is likely due to the SIL-induced increase in the activity of differentiation-antagonizing cell components, such as ERK5. This kinase is under the control of Cot1/Tlp2, and inhibition of Cot1 activity by a specific pharmacological inhibitor 4-(3-chloro-4-fluorophenylamino)-6-(pyridin-3-yl-methylamino-3-cyano-[1-7]-naphthyridine, or by Cot1 siRNA, increases the differentiation by SIL/1,25D combinations. Conversely, over-expression of a Cot1 construct increases the cellular levels of P-ERK5, and SIL/1,25D-induced differentiation and cell cycle arrest are diminished. It appears that reduction in ERK5 activity by inhibition of Cot1 allows SIL to augment the expression of 1,25D-induced differentiation promoting factors and cell cycle regulators such as p27 (Kip1) , which leads to cell cycle arrest. This study shows that in some cell contexts SIL/1,25D can promote expression of both differentiation-promoting and differentiation-inhibiting genes, and that the latter can be neutralized by a highly specific pharmacological inhibitor, suggesting a potential for supplementing treatment of AML with this combination of agents. |
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Authors:
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Xuening Wang; Elzbieta Gocek; Victoria Novik; Jonathan S Harrison; Michael Danilenko; George P Studzinski |
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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 Date: 2010-11-15 |
Journal Detail:
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Title: Cell cycle (Georgetown, Tex.) Volume: 9 ISSN: 1551-4005 ISO Abbreviation: Cell Cycle Publication Date: 2010 Nov |
Date Detail:
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Created Date: 2010-12-08 Completed Date: 2011-03-23 Revised Date: 2011-11-21 |
Medline Journal Info:
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Nlm Unique ID: 101137841 Medline TA: Cell Cycle Country: United States |
Other Details:
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Languages: eng Pagination: 4542-51 Citation Subset: IM |
Affiliation:
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Department of Pathology and Laboratory Medicine, New Jersey Medical School, University of Medicine and Dentistry New Jersey, Newark, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Antineoplastic Combined Chemotherapy Protocols
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therapeutic use* Cell Differentiation Cell Line, Tumor Cyclin-Dependent Kinase Inhibitor p27 / metabolism* G1 Phase Humans Leukemia, Myeloid, Acute / drug therapy, enzymology, metabolism* MAP Kinase Kinase Kinases / antagonists & inhibitors, genetics, metabolism* Mitogen-Activated Protein Kinase 7 / metabolism* Proto-Oncogene Proteins / antagonists & inhibitors, genetics, metabolism* RNA Interference RNA, Small Interfering / metabolism Silymarin / therapeutic use* Up-Regulation Vitamin D / analogs & derivatives*, therapeutic use |
| Grant Support | |
ID/Acronym/Agency:
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R01 CA044722-21/CA/NCI NIH HHS; R01-CA-117942-3/CA/NCI NIH HHS; R01-CA44722/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Proto-Oncogene Proteins; 0/RNA, Small Interfering; 0/Silymarin; 1406-16-2/Vitamin D; 147604-94-2/Cyclin-Dependent Kinase Inhibitor p27; 22888-70-6/silybin; 66772-14-3/1,25-dihydroxyvitamin D; EC 2.7.11.24/Mitogen-Activated Protein Kinase 7; EC 2.7.11.25/MAP Kinase Kinase Kinases; EC 2.7.11.25/MAP3K8 protein, human |
| Comments/Corrections | |
Comment In:
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Cell Cycle. 2010 Dec 1;9(23):4612-3
[PMID:
21260950
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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