Androgens in Health and Disease.pdf - E Library

Chapter 9/Androgen Signaling in Prostatic Neoplasia and Hyperplasia 173
Fig. 2. Receptor-mediated apoptosis: following interaction between a death receptor and its
ligand (in this case, the fas receptor and the fas ligand) (1), pro-caspase-8 is recruited to the DISC
(death-inducing signaling complex), which consists of the receptor, the adaptor molecule FADD
(Fas-associated death-domain-containing molecule), and pro-caspase-8 (2). An active form of
caspase-8 emerges from the DISC (3) and induces apoptosis by two mechanisms. On one side
(4), it directly activates the effector caspases (caspase-3, -6, and -7). These, in turn, cleave
various substrates essential for cell survival and induce the typical biochemical and morphological
phenotype of apoptosis (5). Alternatively, caspase-8 cleaves the proapoptotic Bcl-2 family
member Bid (6). Truncated Bid (t-Bid) complexes to the mitochondrial membrane (7) and
converges to the mitochondrial pathway. A variety of cellular insults converge to functionally
incapacitate the mitochondria (8). These insults are responsible for posttranslational changes of
the proapotpotic Bcl-2 family members Bad (which becomes unphosphorylated), Bax, and Bak
(9). As a result, Bad will become mitochondrial bound and inactivate through heterodimerization
the antiapoptotic Bcl-2 and Bcl-xL. Bax and Bak will homodimerize on the mitochondrial
surface and force functional incapacitation of the mitochondria with obliteration of the transmembrane
potential (∆Ψ m) (10), and translocation to the cytosol of lethal mitochondrial factors
such as cytochrome-c (11), AIF (12), SMAC (16), and endonuclease G (17). In the presence of
APAF-1 and ATP (13), cytochrome-c induces activation of pro-caspase-9 into its active form,
caspase-9 (14), which, in turn, converges into the effector caspases pathway (15). The IAP
proteins inhibit caspase activation and they are inhibited by Smac (16), a mitochondrial protein
that follows cytochrome-c in the cytosol during apoptosis.
events and each activates a specific apical caspase (i.e., caspase-8 is activated by the
extrinsic pathway, and caspase-9 by the intrinsic pathway), the final phase of apoptosis
is thought to be common (204). It includes the activation of caspase-3 and caspase-7 and
destruction of substrates critical for cell survival (207). It is not completely clear which
of these two pathways is activated during castration-induced apoptosis, although observations
by Buttyan and collaborators strongly suggest involvement of the mitochondrial
pathway (discussed next) (208).