Document Detail

Created Gli-1 duplex short-RNA (i-Gli-RNA) eliminates CD44 Hi progenitors of taxol-resistant ovarian cancer cells.
MedLine Citation:
PMID:  20428807     Owner:  NLM     Status:  MEDLINE    
Notch and Hedgehog activate cell-cycle progression of adult and cancer stem cells. Notch is activated by DLL and Jag presents on neighboring cells. We investigated the effects of density of the Notch-activating ligand, Jag-1, and targeting Gli-1, in activation of division of paclitaxel/taxol-resistant, (PTX Res) ovarian cancer cells SKOV3 (SKOV3). We used the specific gamma-presenilin inhibitor, DAPT, to identify the specificity of activating signals for Notch-1 and created 'butterfly-duplex-3548-Gli-1-inhibitory RNA' (i-Gli-1.RNA) to inhibit cell division. To accurately quantify kinetics of division, the expression of CD44 and CD24 was determined in each gated population of divided cells. CD44 High proliferated when activated by Jag-1 Low and poorly when activated by Jag-1 High. DAPT inhibited proliferation of cells activated by Jag-1 Low, and increased proliferation of cells activated by Jag-1 High. Only 5-10% of cells activated by Jag-1 High and Jag-1 Low divided fast, polynomial, and symmetric. i-Gli-1.RNA eliminated more than 50% of the small CD44 High/CD24 Neg cells in divisions 3 and 4. This effect appeared specific compared with cells transfected with negative control siRNA. i-Gli-1.RNA had no effect on large CD44 High/CD24 Neg cells, but inhibited the population of CD44 High/CD24 Low cells. Expansion of CD44 High inversely correlated with Jag-1 density on activating autologous tumor and fibrosarcoma cells. Created i-RNAs may decrease the resting CSC pool. Notch and Gli-1 signals play an important role in proliferation/division and survival of cancer stem cells. Targeting Notch-1 through its enhancer Gl-1, should be significant for novel treatments to eliminate taxol-resistant cancer stem cells (CSC). i.Gli-1 RNA should be more effective if used together with Taxol.
Takashi Mine; Satoko Matsueda; Hui Gao; Yufeng Li; Kwong-Kwok Wong; George E Peoples; Soldano Ferrone; Constantin G Ioannides
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  Oncology reports     Volume:  23     ISSN:  1791-2431     ISO Abbreviation:  Oncol. Rep.     Publication Date:  2010 Jun 
Date Detail:
Created Date:  2010-04-29     Completed Date:  2010-09-30     Revised Date:  2014-07-29    
Medline Journal Info:
Nlm Unique ID:  9422756     Medline TA:  Oncol Rep     Country:  Greece    
Other Details:
Languages:  eng     Pagination:  1537-43     Citation Subset:  IM    
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MeSH Terms
Antigens, CD44 / metabolism*
Antineoplastic Agents, Phytogenic / pharmacology
Blotting, Western
Calcium-Binding Proteins / genetics,  metabolism
Cell Line, Tumor
Cell Proliferation
Drug Resistance, Neoplasm*
Fibrosarcoma / drug therapy,  genetics,  metabolism*
Flow Cytometry
Intercellular Signaling Peptides and Proteins / genetics,  metabolism
Membrane Proteins / genetics,  metabolism
Ovarian Neoplasms / drug therapy,  genetics,  metabolism*
Paclitaxel / pharmacology*
RNA, Messenger / genetics
RNA, Small Interfering / genetics*
Reverse Transcriptase Polymerase Chain Reaction
Stem Cells / drug effects
Transcription Factors / genetics*,  metabolism
Grant Support
P01 CA109688/CA/NCI NIH HHS; R01 CA110249/CA/NCI NIH HHS; R01 CA138188/CA/NCI NIH HHS
Reg. No./Substance:
0/Antigens, CD44; 0/Antineoplastic Agents, Phytogenic; 0/CD44 protein, human; 0/Calcium-Binding Proteins; 0/GLI1 protein, human; 0/Intercellular Signaling Peptides and Proteins; 0/Membrane Proteins; 0/RNA, Messenger; 0/RNA, Small Interfering; 0/Transcription Factors; 134324-36-0/Serrate proteins; 33069-62-4/Paclitaxel

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