Document Detail

PTEN augments SPARC suppression of proliferation and inhibits SPARC-induced migration by suppressing SHC-RAF-ERK and AKT signaling.
MedLine Citation:
PMID:  20472716     Owner:  NLM     Status:  MEDLINE    
SPARC (secreted protein acidic and rich in cysteine) is expressed in all grades of astrocytoma, including glioblastoma (GBM). SPARC suppresses glioma growth but promotes migration and invasion by mediating integrin and growth factor receptor-regulated kinases and their downstream effectors. PTEN (phosphatase and tensin homolog deleted on chromosome 10), which is commonly lost in primary GBMs, negatively regulates proliferation and migration by inhibiting some of the same SPARC-mediated signaling pathways. This study determined whether PTEN reconstitution in PTEN-mutant, SPARC-expressing U87MG cells could further suppress proliferation and tumor growth but inhibit migration and invasion in SPARC-expressing cells in vitro and in vivo, and thereby prolong survival in animals with xenograft tumors. In vitro, PTEN reduced proliferation and migration in both SPARC-expressing and control cells, with a greater suppression in SPARC-expressing cells. PTEN reconstitution suppressed AKT activation in SPARC-expressing and control cells but suppressed the SHC-RAF-ERK signaling pathway only in SPARC-expressing cells. Importantly, coexpression of SPARC and PTEN resulted in the smallest, least proliferative tumors with reduced invasive capacity and longer animal survival. Furthermore, direct inhibition of the AKT and SHC-RAF-ERK signaling pathways suppressed the proliferation and migration of SPARC-expressing cells in vitro. These findings demonstrate that PTEN reconstitution or inhibition of signaling pathways that are activated by the loss of PTEN provide potential therapeutic strategies to inhibit SPARC-induced invasion while enhancing the negative effect of SPARC on tumor growth.
Stacey L Thomas; Ridwan Alam; Nancy Lemke; Lonni R Schultz; Jorge A Gutiérrez; Sandra A Rempel
Related Documents :
23413906 - Effect of immune modulation therapy on cardiac function and t-bet/gata-3 gene expressio...
22017396 - Increased levels of cox-2 in oral lichen planus supports an autoimmune cause of the dis...
20473866 - Alpha-fetoprotein: a new member of intracellular signal molecules in regulation of the ...
23859016 - Enhanced 5-fluorouracil cytotoxicity in high cox-2 expressing hepatocellular carcinoma ...
13680226 - Molecular cloning and developmental expression of two chloride intracellular channel (c...
21410056 - Mrna levels of two different enzymes in hepatocellular carcinoma.
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-05-14
Journal Detail:
Title:  Neuro-oncology     Volume:  12     ISSN:  1523-5866     ISO Abbreviation:  Neuro-oncology     Publication Date:  2010 Sep 
Date Detail:
Created Date:  2010-08-19     Completed Date:  2010-12-02     Revised Date:  2013-05-29    
Medline Journal Info:
Nlm Unique ID:  100887420     Medline TA:  Neuro Oncol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  941-55     Citation Subset:  IM    
Barbara Jane Levy Laboratory of Molecular Neuro-Oncology, Hermelin Brain Tumor Center, Department of Neurosurgery, Henry Ford Hospital, Detroit, Michigan 48202, USA.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Blotting, Western
Brain Neoplasms / metabolism*,  pathology
Cell Line, Tumor
Cell Movement / physiology
Cell Proliferation
Extracellular Signal-Regulated MAP Kinases / metabolism
Glioblastoma / metabolism*,  pathology
Osteonectin / metabolism*
PTEN Phosphohydrolase / metabolism*
Proto-Oncogene Proteins c-akt / metabolism
Shc Signaling Adaptor Proteins / metabolism
Signal Transduction / physiology*
Xenograft Model Antitumor Assays
raf Kinases / metabolism
Grant Support
Reg. No./Substance:
0/Osteonectin; 0/Shc Signaling Adaptor Proteins; EC Proteins c-akt; EC Kinases; EC Signal-Regulated MAP Kinases; EC protein, human; EC Phosphohydrolase

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

Previous Document:  HDMX regulates p53 activity and confers chemoresistance to 3-bis(2-chloroethyl)-1-nitrosourea.
Next Document:  Occurrence of inflammatory bowel disease during treatment of juvenile idiopathic arthritis with etan...