| Sonic hedgehog signaling regulates Bcr-Abl expression in human chronic myeloid leukemia cells. | |
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MedLine Citation:
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PMID: 22397755 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: JOURNAL ARTICLE Date: 2012-2-16 |
Journal Detail:
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Title: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie Volume: - ISSN: 1950-6007 ISO Abbreviation: - Publication Date: 2012 Feb |
Date Detail:
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Created Date: 2012-3-8 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8213295 Medline TA: Biomed Pharmacother Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Copyright © 2012 Elsevier Masson SAS. All rights reserved. |
Affiliation:
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Department of Biochemical Science and Technology, National Chiayi University, Chiayi 600, Taiwan. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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