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

Qian J, Zou Y, Rahman JS, Lu B, Massion PP
Mol Cancer Ther. 2009 8 (1): 101-9

PMID: 19139118 · PMCID: PMC3110728 · 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.

MeSH Terms (17)

Adenocarcinoma Apoptosis Apoptosis Regulatory Proteins Bcl-2-Like Protein 11 bcl-X Protein Cell Line, Tumor Chromones Humans Lung Neoplasms Membrane Proteins Morpholines Phosphatidylinositol 3-Kinases Protein Kinase Inhibitors Proto-Oncogene Proteins Proto-Oncogene Proteins c-akt Signal Transduction Substrate Specificity

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