A. Nesterov et al., Elevated Akt activity protects the prostate cancer cell line LNCaP from TRAIL-induced apoptosis, J BIOL CHEM, 276(14), 2001, pp. 10767-10774
We find that the prostate cancer cell lines ALVA-31, PC-3, and DU 145 are h
ighly sensitive to apoptosis induced by TRAIL ((t) under bar umor-necrosis
factor-(r) under bar elated (a) under bar poptosis-(i) under bar nducing (l
) under bar igand), while the cell lines TSU-Prl and JCA-1 are moderately s
ensitive, and the LNCaP cell line is resistant. LNCaP cells lack active lip
id phosphatase PTEN, a negative regulator of the phosphatidylinositol (PI)
3-kinase/Akt pathway, and demonstrate a high constitutive Akt activity. Inh
ibition of PI 3-kinase using wortmannin and LY-294002 suppressed constituti
ve Akt activity and sensitized LNCaP cells to TRAIL, Treatment of LNCaP cel
ls with TRAIL alone induced cleavage of the caspase 8 and XIAP proteins. Ho
wever, processing of BID, mitochondrial release of cytochrome c, activation
of caspases 7 and 9, and apoptosis did not occur unless TRAIL was combined
with either wortmannin, LY-294002, or cycloheximide, Blocking cytochrome c
release by Bcl-2 overexpression rendered LNCaP cells resistant to TRAIL pl
us wortmannin treatment but did not affect caspase 8 or BID processing. Thi
s indicates that in these cells mitochondria are required for the propagati
on rather than the initiation of the apoptotic cascade, Infection of LNCaP
cells with an adenovirus expressing a constitutively active Akt reversed th
e ability of wortmannin to potentiate TRAIL-induced BID cleavage. Thus, the
PI 5-kinase-dependent blockage of TRAIL-induced apoptosis in LNCaP cells a
ppears to be mediated by Akt through the inhibition of BID cleavage.