Antiapoptotic signaling in LNCaP prostate cancer cells: a survival signaling pathway independent of phosphatidylinositol 3'-kinase and Akt/protein kinase B.
Constitutive activation of the phosphatidylinositol 3'-kinase (PI3 kinase)-Akt/protein kinase B (PKB) "survival signaling" pathway is a likely mechanism by which many cancers become refractory to cytotoxic therapy. In LNCaP prostate cancer cells, the PTEN phosphoinositide phosphatase is inactivated, leading to constitutive activation of Akt/PKB and resistance to apoptosis. However, apoptosis and inactivation of Akt/PKB can be induced in these cells by treatment with PI3 kinase inhibitors. Surprisingly, androgen, epidermal growth factor, or serum can protect these cells from apoptosis, even in the presence of PI3 kinase inhibitors and without activation of Akt/PKB, indicating the activity of a novel, Akt/PKB-independent survival pathway. This pathway blocks apoptosis at a level prior to caspase 3 activation and release of cytochrome c from mitochondria.
Carson
J P
JP
Department of Microbiology and Cancer Center, University of Virginia Health Sciences Center, Charlottesville 22908, USA.
Kulik
G
G
Weber
M J
MJ
D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D016895:Culture Media, Serum-Free; D003574:Cytochrome c Group / Q000502:physiology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D006801:Humans; D008297:Male; D015741:Metribolone / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D014407:Tumor Cells, Cultured
D053148:Caspase 3; D020169:Caspases; D016895:Culture Media, Serum-Free; D003574:Cytochrome c Group; D004815:Epidermal Growth Factor; D015741:Metribolone; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; C494918:AKT1 protein, human; C505407:CASP3 protein, human