Document Detail

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).
MedLine Citation:
PMID:  21084834     Owner:  NLM     Status:  MEDLINE    
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.
Xuening Wang; Elzbieta Gocek; Victoria Novik; Jonathan S Harrison; Michael Danilenko; George P Studzinski
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-11-15
Journal Detail:
Title:  Cell cycle (Georgetown, Tex.)     Volume:  9     ISSN:  1551-4005     ISO Abbreviation:  Cell Cycle     Publication Date:  2010 Nov 
Date Detail:
Created Date:  2010-12-08     Completed Date:  2011-03-23     Revised Date:  2014-09-11    
Medline Journal Info:
Nlm Unique ID:  101137841     Medline TA:  Cell Cycle     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4542-51     Citation Subset:  IM    
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MeSH Terms
Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
Cell Differentiation
Cell Line, Tumor
Cyclin-Dependent Kinase Inhibitor p27 / metabolism*
G1 Phase
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*
Vitamin D / analogs & derivatives*,  therapeutic use
Grant Support
R01 CA044722/CA/NCI NIH HHS; R01 CA044722-21/CA/NCI NIH HHS; R01-CA-117942-3/CA/NCI NIH HHS; R01-CA44722/CA/NCI NIH HHS
Reg. No./Substance:
0/Proto-Oncogene Proteins; 0/RNA, Small Interfering; 0/Silymarin; 1406-16-2/Vitamin D; 147604-94-2/Cyclin-Dependent Kinase Inhibitor p27; 4RKY41TBTF/silybin; 66772-14-3/1,25-dihydroxyvitamin D; EC Protein Kinase 7; EC Kinase Kinase Kinases; EC protein, human
Comment In:
Cell Cycle. 2010 Dec 1;9(23):4612-3   [PMID:  21260950 ]

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