Synergy between phosphatidylinositol 3-kinase/Akt pathway and Bcl-xL in the control of apoptosis in adenocarcinoma cells of the lung

• Published in: Molecular cancer therapeutics 2009-01, Vol.8 (1), p.101-109
• Main Authors: Qian, Jun, Zou, Yong, Rahman, Jamshedur S M, Lu, Bo, Massion, Pierre P
• Format: Article
• Language: English
• Subjects: adenocarcinoma; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; apoptosis; Apoptosis - drug effects; Apoptosis Regulatory Proteins - metabolism; Bcl-2-Like Protein 11; bcl-X Protein - metabolism; Bcl-xL; Cell Line, Tumor; Chromones - pharmacology; Humans; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Membrane Proteins - metabolism; Morpholines - pharmacology; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - metabolism; PI3K/Akt pathway; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction - drug effects; Substrate Specificity
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-08-0973

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. [Mol Cancer Ther 2009;8(1):101–9]