Carson J P, Kulik G, Weber M J
Department of Microbiology and Cancer Center, University of Virginia Health Sciences Center, Charlottesville 22908, USA.
Cancer Res. 1999 Apr 1;59(7):1449-53.
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.
磷脂酰肌醇3'-激酶（PI3激酶）-Akt/蛋白激酶B（PKB）“存活信号”通路的组成性激活可能是许多癌症对细胞毒性疗法产生耐药性的一种机制。在LNCaP前列腺癌细胞中，PTEN磷酸肌醇磷酸酶失活，导致Akt/PKB的组成性激活和对凋亡的抵抗。然而，用PI3激酶抑制剂处理可诱导这些细胞发生凋亡并使Akt/PKB失活。令人惊讶的是，雄激素、表皮生长因子或血清可保护这些细胞免于凋亡，即使在存在PI3激酶抑制剂且Akt/PKB未激活的情况下也是如此，这表明存在一条新的、不依赖Akt/PKB的存活通路。该通路在半胱天冬酶3激活和细胞色素c从线粒体释放之前的水平阻断凋亡。
