TRAIL-Induced Apoptosis - A Prostate Cancer Therapy

摘要

TRAIL induces apoptosis in five of six prostate cancer cell lines. The cell line LNCaP is resistant to TRAIL treatment. High constitutive expression of AKT was found in LNCaP cells, and suppression of AKT activity by the PI-3 kinase inhibitors wortmanin and Ly 294002 or dominant negative Akt expression renders LNCaP cells sensitive to TRAIL. Infection of LNCaP cells with a constitutively active AKT reverses the wortmanin effect. Thus, elevated AKT protects LNCaP cells from TRAIL-induced apoptosis. Overexpression of Bcl-2 or bcl-X1 in LNCaP cells inhibits cytochrome c release from mitochondria when TRAIL is used in combination with wortmanin, suggesting that the mitochondria mediated apoptosis pathway is crucial. Expression of other Bcl-2 family members such as BAX, BAK and caspases inhibitor XIAP does not change after TRAIL treatment. Heterozygous deficiency of MnSOD renders smooth muscle cells more sensitive TRAIL, indicating a possible role of mitochondria superoxide production in TRAIL induced apoptosis. In addition, TRAIL induces apoptosis in human angiomyolipoma cells - a cell culture model system for human lymphangiomyomatosis (LAM) , suggesting a potential role for TRAIL in therapy for human LAM.