Document Detail

Urokinase plasminogen activator receptor and/or matrix metalloproteinase-9 inhibition induces apoptosis signaling through lipid rafts in glioblastoma xenograft cells.
MedLine Citation:
PMID:  20716639     Owner:  NLM     Status:  MEDLINE    
Small interfering RNA (siRNA)-mediated transcriptional knockdown of urokinase plasminogen activator receptor (uPAR) and matrix metalloproteinase-9 (MMP-9), alone or in combination, inhibits uPAR and/or MMP-9 expression and induces apoptosis in the human glioblastoma xenograft cell lines 4910 and 5310. siRNA against uPAR (pU-Si), MMP-9 (pM-Si), or both (pUM-Si) induced apoptosis and was associated with the cleavage of caspase-8, caspase-3, and poly(ADP-ribose) polymerase. Furthermore, protein levels of the Fas receptor (APO-1/CD-95) were increased following transcriptional inactivation of uPAR and/or MMP-9. In addition, Fas siRNA against the Fas death receptor blocked apoptosis induced by pU-Si, pM-Si, or pUM-Si, thereby indicating the role for Fas signaling in pU-Si-, pM-Si-, or pUM-Si-mediated apoptotic cell death of human glioma xenograft cells. Thus, transcriptional inactivation of uPAR and/or MMP-9 enhanced localization of Fas death receptor, Fas-associated death domain-containing protein, and procaspase-8 into lipid rafts. Additionally, disruption of lipid rafts with methyl β cyclodextrin prevented Fas clustering and pU-Si-, pM-Si-, or pUM-Si-induced apoptosis, which is indicative of coclustering of Fas death receptor into lipid rafts in the glioblastoma xenograft cell lines 4910 and 5310. These data indicate the crucial role of the clusters of apoptotic signaling molecule-enriched rafts in programmed cell death, acting as concentrators of death receptors and downstream signaling molecules, and as the linchpin from which a potent death signal is launched in uPAR- and/or MMP-9-downregulated cells.
Chandramu Chetty; Sajani S Lakka; Praveen Bhoopathi; Christopher S Gondi; Krishna Kumar Veeravalli; Daniel Fassett; Jeffrey D Klopfenstein; Dzung H Dinh; Meena Gujrati; Jasti S Rao
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2010-08-17
Journal Detail:
Title:  Molecular cancer therapeutics     Volume:  9     ISSN:  1538-8514     ISO Abbreviation:  Mol. Cancer Ther.     Publication Date:  2010 Sep 
Date Detail:
Created Date:  2010-09-10     Completed Date:  2011-02-17     Revised Date:  2014-09-20    
Medline Journal Info:
Nlm Unique ID:  101132535     Medline TA:  Mol Cancer Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2605-17     Citation Subset:  IM    
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MeSH Terms
Antigens, CD95 / metabolism
Apoptosis / genetics
Brain Neoplasms / enzymology,  genetics,  pathology,  therapy*
Caspase 8 / metabolism
Cell Line, Tumor
Glioblastoma / genetics,  metabolism,  pathology,  therapy*
Matrix Metalloproteinase 9 / genetics,  metabolism
Matrix Metalloproteinase Inhibitors*
Membrane Microdomains / genetics,  metabolism*
Mice, Nude
RNA, Small Interfering / administration & dosage*,  genetics
Receptors, Urokinase Plasminogen Activator / antagonists & inhibitors*,  genetics,  metabolism
Signal Transduction
Transcriptional Activation
Transplantation, Heterologous
Xenograft Model Antitumor Assays
Grant Support
Reg. No./Substance:
0/Antigens, CD95; 0/Matrix Metalloproteinase Inhibitors; 0/RNA, Small Interfering; 0/Receptors, Urokinase Plasminogen Activator; EC 3.4.22.-/Caspase 8; EC Metalloproteinase 9

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