Document Detail


Synergy between phosphatidylinositol 3-kinase/Akt pathway and Bcl-xL in the control of apoptosis in adenocarcinoma cells of the lung.
MedLine Citation:
PMID:  19139118     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Adenocarcinomas of the lung commonly show an increase in the activity of phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, yet many are resistant to apoptosis induced by the inhibition of PI3K. We hypothesized that Bcl-xL would have a synergistic effect on the apoptotic response induced by inhibition of the PI3K/Akt pathway in lung adenocarcinoma. To test this, we examined the effect of the PI3K inhibitor (LY294002) on lung adenocarcinoma cell lines expressing varying levels of Bcl-xL. We found that cells that overexpress Bcl-xL are resistant to LY294002-induced apoptosis, whereas cells that express little Bcl-xL readily are not. Restoring Bcl-xL expression in cells that express low level of Bcl-xL conferred resistance to apoptosis in response to LY294002. The simultaneous inhibition of the PI3K/Akt pathway by LY294002 or Akt1 small interfering RNA and Bcl-xL function by ABT-737 or Bcl-xL small interfering RNA greatly enhanced the apoptotic response. Moreover, this response was associated with the induction of proapoptotic BH3-only Bcl-2 family member Bim. Our data suggest that PI3K/Akt and Bcl-xL pathways control cell death in lung adenocarcinoma cells in a synergistic manner. Modulation of Bcl-xL expression may represent one important strategy to optimize the efficacy of therapeutic agents targeting the PI3K/Akt pathway in adenocarcinoma of the lung.
Authors:
Jun Qian; Yong Zou; Jamshedur S M Rahman; Bo Lu; Pierre P Massion
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Molecular cancer therapeutics     Volume:  8     ISSN:  1535-7163     ISO Abbreviation:  Mol. Cancer Ther.     Publication Date:  2009 Jan 
Date Detail:
Created Date:  2009-01-13     Completed Date:  2009-02-19     Revised Date:  2013-12-30    
Medline Journal Info:
Nlm Unique ID:  101132535     Medline TA:  Mol Cancer Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  101-9     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Adenocarcinoma / metabolism*,  pathology
Apoptosis* / drug effects
Apoptosis Regulatory Proteins / metabolism
Cell Line, Tumor
Chromones / pharmacology
Humans
Lung Neoplasms / metabolism*,  pathology
Membrane Proteins / metabolism
Morpholines / pharmacology
Phosphatidylinositol 3-Kinases / antagonists & inhibitors,  metabolism*
Protein Kinase Inhibitors / pharmacology
Proto-Oncogene Proteins / metabolism
Proto-Oncogene Proteins c-akt / metabolism*
Signal Transduction* / drug effects
Substrate Specificity
bcl-X Protein / metabolism*
Grant Support
ID/Acronym/Agency:
R01 CA102353/CA/NCI NIH HHS; R01 CA102353/CA/NCI NIH HHS; R01 CA102353-01A2/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Apoptosis Regulatory Proteins; 0/Bcl-2-like protein 11; 0/Chromones; 0/Membrane Proteins; 0/Morpholines; 0/Protein Kinase Inhibitors; 0/Proto-Oncogene Proteins; 0/bcl-X Protein; 154447-36-6/2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC 2.7.11.1/Proto-Oncogene Proteins c-akt
Comments/Corrections

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


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