Document Detail


Vitamin D resistance in RAS-transformed keratinocytes: mechanism and reversal strategies.
MedLine Citation:
PMID:  11121228     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Human retinoid X receptor alpha (hRXRalpha) plays a critical role in DNA binding and transcriptional activity through its heterodimeric association with several members of the nuclear receptor superfamily, including the vitamin D receptor (VDR). Several cancer cell lines derived from different tissues have been shown to be resistant to the growth-inhibitory action of 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], the biologically active metabolite of vitamin D(3). Here we show that in RAS-transformed keratinocytes, Ser260 of hRXRalpha is phosphorylated through the RAS-RAF-MAP kinase cascade. This phosphorylation event results in the inhibition of vitamin D signaling via VDR/hRXRalpha heterodimers. Strategies to reverse this resistance include the use of the MAP kinase inhibitor, PD098059, and a non-phosphorylatable hRXRalpha mutant, Ala260, which completely abolishes RXR phosphorylation and restores the function of both 1,25(OH)(2)D(3) and a specific RXR ligand, LG1069 (4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphtalenyl)ethenyl]-benzoic acid). In addition, we show that a vitamin D analog with low calcemic activity (EB1089) is more potent than 1,25(OH)(2)D(3) in inhibiting cancer cell growth in this system. Targeted therapy with selective analogs such as EB1089, in combination with the inhibition of phosphorylation of the RXR, could play a critical role in the development of strategies for cancer treatment.
Authors:
C Solomon; R Kremer; J H White; J S Rhim
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Radiation research     Volume:  155     ISSN:  0033-7587     ISO Abbreviation:  Radiat. Res.     Publication Date:  2001 Jan 
Date Detail:
Created Date:  2001-01-26     Completed Date:  2001-03-01     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  0401245     Medline TA:  Radiat Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  156-162     Citation Subset:  IM; S    
Affiliation:
Department of Medicine, Royal Victoria Hospital, McGill University, Montreal, Quebec, H3A 1A1, Canada.
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MeSH Terms
Descriptor/Qualifier:
Cell Division / drug effects
Cell Transformation, Neoplastic*
Dimerization
Drug Resistance
Genes, ras
Humans
Keratinocytes / drug effects*,  enzymology,  metabolism
MAP Kinase Signaling System / physiology
Mitogen-Activated Protein Kinases / metabolism*
Phosphorylation
Receptors, Calcitriol / genetics,  metabolism,  physiology
Receptors, Cell Surface / metabolism*,  physiology
Receptors, Cytoplasmic and Nuclear / metabolism*,  physiology
Receptors, Melatonin
Signal Transduction / physiology
Vitamin D / antagonists & inhibitors,  pharmacology*
Chemical
Reg. No./Substance:
0/Receptors, Calcitriol; 0/Receptors, Cell Surface; 0/Receptors, Cytoplasmic and Nuclear; 0/Receptors, Melatonin; 1406-16-2/Vitamin D; EC 2.7.11.24/Mitogen-Activated Protein Kinases

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