Document Detail


Sonic hedgehog signaling regulates Bcr-Abl expression in human chronic myeloid leukemia cells.
MedLine Citation:
PMID:  22397755     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
PURPOSE: Bcr-Abl fusion protein activates tyrosine kinase, resulting in the proliferation of leukemia cells, especially chronic myeloid leukemia (CML) cells. Imatinib (IM) effectively targets Bcr-Abl tyrosine kinase, but development of resistance to IM occurs with varying frequency.
METHODS: Elucidation of the common regulatory pathway upstream of Bcr-Abl in IM-sensitive and IM-resistant CML cells is important for developing novel therapeutics against CML.
RESULTS: This study demonstrated that IM preferentially inhibited the viability and Bcr-Abl expression in IM-sensitive K562 (K562) cells, but not in Bcr-Abl overexpressing IM-resistant K562 (K562R) cells. Both K562 and K562R cells expressed Shh preproprotein, cleaved Shh C-terminal and N-terminal peptides, as well as mRNA level of major Shh signaling molecules, including sonic hedgehog (Shh), patched (PTCH), smoothened (Smo) and Gli-1. Moreover, Gli-1 translocation into nucleus was evident in these two cell lines, suggesting that both K562 and K562R cells possess activated and major components of the Shh signaling pathway. Silencing of Gli-1 by interference RNA was accompanied by inhibition of Bcr-Abl protein expression. Pharmacological suppression of Bcr-Abl expression was restored by the Smo agonist purmorpharmine. Treatment of Shh peptide in both K562 and K562R cells not only increased Shh and Gli-1 expression, but also up-regulated Bcr-Abl expression. Resveratrol, a known Bcr-Abl inhibitor, reduced Gli-1 activation and inhibited the viability of CML cells.
CONCLUSIONS: Shh signaling may regulate Bcr-Abl expression in human chronic myeloid leukemia cells. Novel compounds inhibiting both Shh signaling and Bcr-Abl expression, such as resveratrol, may have potential to be effective agents against CML independent of IM resistance.
Authors:
Hui-Fen Liao; Yu-Chieh Su; Zhi-Yu Zheng; Chang Jhih Cai; Ming-Hung Hou; K S Clifford Chao; Yu-Jen Chen
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-02-16
Journal Detail:
Title:  Biomedicine & pharmacotherapy = Biomédecine & pharmacothérapie     Volume:  66     ISSN:  1950-6007     ISO Abbreviation:  Biomed. Pharmacother.     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-07-20     Completed Date:  2013-01-04     Revised Date:  2013-06-03    
Medline Journal Info:
Nlm Unique ID:  8213295     Medline TA:  Biomed Pharmacother     Country:  France    
Other Details:
Languages:  eng     Pagination:  378-83     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Elsevier Masson SAS. All rights reserved.
Affiliation:
Department of Biochemical Science and Technology, National Chiayi University, Chiayi 600, Taiwan.
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents / pharmacology
Cell Survival / drug effects
Drug Resistance, Neoplasm
Fusion Proteins, bcr-abl / genetics*
Hedgehog Proteins / genetics,  metabolism*
Humans
K562 Cells
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*,  genetics,  pathology
Piperazines / pharmacology*
Pyrimidines / pharmacology*
RNA Interference
RNA, Messenger / metabolism
RNA, Small Interfering / administration & dosage
Signal Transduction / drug effects
Stilbenes / pharmacology*
Up-Regulation / drug effects
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Fusion Proteins, bcr-abl; 0/Hedgehog Proteins; 0/Piperazines; 0/Pyrimidines; 0/RNA, Messenger; 0/RNA, Small Interfering; 0/SHH protein, human; 0/Stilbenes; BKJ8M8G5HI/imatinib; Q369O8926L/resveratrol

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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