Fig. 2

Different apoptotic pathways are modulated by PEDF. 1. PEDF contributes to apoptosis in endothelial cells via the extrinsic FAS/FASL pathway [120] 2. PEDF can sequentially induce the expression of PPARγ and p53 in endothelial cells. Stimulated p53 increases pro-apoptotic PUMA, inducing this protein to initiate the intrinsic pathway to apoptosis [130 ] 3. Also, PEDF mediates endothelial cell apoptosis through JNK activation, leading to cellular FLICE-like inhibitory protein (c-FLIP) blockade, which propels cells into a pro-apoptotic state [130]. 4. PEDF can utilize the BCL2 family of proteins from the intrinsic pathway to stimulate apoptosis in tumors. Notably, activated caspase-8 stimulates apoptosis via two parallel cascades: it either directly cleaves and activates caspase-3, or it can cleave BID, a pro-apoptotic BCL2 family protein. tBID activation of BAX results in oligomerization of BAX on the cell membrane [146]. Anti-apoptotic BCL2 protein inhibits BAX oligomerization by sequestering tBID. The ratio of BAX/BCL2 may be more important than either promoters alone in determining apoptosis [147]. (→) means protein activation, and (—) means protein inhibition