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 mechani sm by which many cancers become refractory to cytotoxic therapy. In LNCaP p rostate 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 ran be induced in these cel ls by treatment with PI3 kinase inhibitors. Surprisingly, androgen, epiderm al growth factor, or serum can protect these cells from apoptosis, even in the presence of PI3 kinase inhibitors and without activation of Akt/PKB, in dicating the activity of a novel, Akt/PKB-independent survival pathway. Thi s pathway blocks apoptosis at a level prior to caspase 3 activation and rel ease of cytochrome c from mitochondria.