Carotenoids as Modulators of Molecular Pathways Involved in Cell Proliferation and Apoptosis - Carotenoids: Physical, Chemical, and Biological Functions and Properties - page 477

PCNA over-expression, and diminished apoptosis) were associated with reduced plasma IGFBP-3
concentrations and increased IGF-1/IGFBP-3 ratios. Such changes signii cantly affected the
status of cell proliferation and apoptosis in the lung of ferrets. Smoke exposure signii cantly
decreased cleaved caspase-3 protein and increased PCNA. Furthermore, smoke exposure sup-
pressed Bad-mediated apoptosis by inducing the phoshorylation of Bad at both Ser136 and Ser112.
These smoke-induced changes were prevented by lycopene supplementation in a dose-dependent
manner. The carotenoid was able to increase IGFBP-3 levels and decrease IGF-1/IGFBP-3 ratio.
Moreover, it decreased Bad phosphorylation at both Ser136 and Ser112 and increased cleaved
caspase-3, preventing cigarette smoke-induced squamous metaplasia and the increase in PCNA
(Liu et al., 2003).
A recent in vitro study also suggests that the modulation of Akt pathway may have a key role
in the pro-apoptotic effects of lycopene under smoke conditions (Palozza et al., 2005b). In fact,
while RAT-1 i broblasts exposed to cigarette smoke condensate (TAR) exhibited high levels of
phosphorylated Akt, cells exposed to a combination of TAR and lycopene strongly decreased them.
Moreover, the exposition of RAT-1 i broblasts to TAR alone suppressed Bad-mediated apoptosis by
inducing the phosphorylation of Bad at Ser136. Conversely, lycopene was able to completely pre-
vent the phosphorylation of Bad induced by TAR, coni rming in vitro the results obtained in vivo
by Liu et al. (2003). In our laboratory, similar results have been recently found in the human pros-
tate DU-145 cancer cells exposed to lycopene in association with TAR. The carotenoid was able to
prevent TAR-induced Akt and Bad phosphorylation. Moreover, in the same study, the expression
of the heat shock protein, Hsp90, was increased following TAR exposure (Palozza et al., 2005a).
Such an increase was counteracted by lycopene. This i nding is particularly interesting in view of
a previous report showing that Hsp90 maintains Akt activity by binding to Akt and by preventing
PP2A-dependent dephosphorylation of Akt (Sato et al., 2000). Moreover, Hsp90 has been reported
to prevent proteasome-dependent degradation of PDK1, which is known to activate Akt (Fujita
et al., 2002). On the other hand, the i nding that lycopene is able to counteract the effect of TAR
on Hsp90 is not surprising in view of the fact that heat shock proteins increase as a consequence of
oxidative stress, including smoke (Pinot et al., 1997) and that lycopene acts as a potent antioxidant
(Conn et al., 1991; Di Mascio et al., 1989). The modulation of Hsp90 by lycopene under smoke
conditions could be a further suggestive intracellular mechanism to explain the modulatory activity
of lycopene on Bad.
22.13.2 P LATELET -D ERIVED G ROWTH F ACTOR -BB
In a recent study, it has been found that lycopene inhibited PDGF-BB-induced signaling and cell
migration in human cultured skin i broblasts through a novel mechanism of action, i.e., direct bind-
ing to PDGF-BB. The trapping of PDGF by lycopene also compromised melanoma-induced i bro-
blast migration and attenuated signaling transduction in i broblasts simulated by melanoma-derived
conditioned medium, suggesting that lycopene may interfere with tumor-stroma interactions. The
trapping activity of lycopene on PDGF suggests that it may act as an inhibitor on stromal cells,
tumor cells and their interactions, which may contribute to its antitumor activity (Wu et al., 2007).
22.14 MODULATION OF HORMONES
Androgens are implicated in prostatic neoplasia, including benign prostatic hyperplasia and pros-
tate cancer. Studies in prostate suggest that 5-a-dihydrotestosterone is the principal androgen
responsible for both normal and hyperplastic growth of the prostate gland. 5-a-dihydrotestosterone
is produced from testosterone by steroid 5-a-reductase. It has been recently reported that lycopene
reduced the expression of 5-a-reductase I in prostate tumors in the rat MatLyLu Dunning prostate
cancer model (Siler et al., 2004). As a consequence of this down-regulation, several androgen
target genes were drastically downregulated, including cystatin-related protein 1 and 2, prostatic