Lycopene Oxidation, Uptake, and Activity in Human Prostate Cell Cultures - Carotenoids: Physical, Chemical, and Biological Functions and Properties - page 456

21.9.2 L YCOPENE M ODULATION OF R ETINOID R ECEPTOR S IGNALING
Retinoic acid is the natural ligand for the RAR and the heterodimer RAR/RXR DNA receptors
that activate the response elements, RAR response element (RARE) and RXR response element
(RXRE) which, in turn, regulate the expression of a wide range of target genes engaged in cellular
differentiation and the local modulation of chromatin structure. RARE and RXRE activations are
generally considered antiproliferative. Retinoids inhibit the growth of several prostate cancer cell
lines and suppress the development of prostate carcinogenesis in some animal models but seem to
be more effective when combined with other chemopreventive agents. Surprisingly, antagonists to
RAR were even more effective (Pasquali et al. 2006). The structural analysis of the

ligand-binding pockets of both RAR and RXR retinoid receptors indicates the need for a negatively
charged ligand, which is attracted to a cluster of positively charged amino acids (two arginines and
three lysines). The pocket for RAR appears to be larger than that of RXR, which may explain why
both retinoic acid and 9- cis -retinoic acid activate RAR but only 9- cis -retinoic acid activates RXR.
Interestingly, some of the synthetic retinoids appear to have no resemblance to linear retinoic acid
but all have a hydrophobic moiety that mimicks the

β and RAR γ

-ionone ring of the two natural ligands. A
good ligand i t changes the conformation of these receptors such that they are able to recruit crucial
enzymes and factors that regulate DNA transcription (Klaholz and Moras 1998). Differences in the
conformation of the response elements on different genes explain the wide variation in physiological
responses to various retinoid-like ligands.
Investigators have focused on the more polar metabolites of lycopene as possible RAR ligands.
Eighty percent of radio-labeled lycopene fed to rats accumulated in the prostate as polar products
and the level of lycopenoids, such as 10

β

-lycopenal, was comparable to retinoic acid concentrations
in the ferret lung (Lindshield et al. 2007). Acycloretinal (20

′

lycopenal) is a common in vitro product
formed with the cleavage at the central double bond of lycopene. Acycloretinal has been shown to be
converted to acycloretinoic acid spontaneously in vitro and by rat liver homogenates (Nagao 2004).
Stahl and coworkers found that acycloretinoic acid was a much weaker ligand (50

′

μ M) compared

to retinoic acid (0.1 2 promoter and while acycloretinoic

acid stimulated gap -junction communication in fetal skin i broblasts and stabilized Connexin 43
mRNA, it was 10-fold less effective than retinoic acid (Stahl et al. 2000). Vine et al. found that
RAR

μ M) for the transactivation of the RAR β

is the responsive nuclear receptor for the retinoid up-regulation of Connexin 43 expression
but lycopene and other non-provitamin A carotenoids act in a manner independent of RARs on the
RARE. They did not directly evaluate acycloretinoic acid (Vine et al. 2005). Ben-Dor et al. used a
transient transfection system to explore retinoic acid versus acycloretinoic acid as ligands for RAR
and RXR, and the extent of transactivation of reporter genes containing three different RAREs.
Although acycloretinoic acid and retinoic acid (5

α

M, respectively) were equally potent in producing
G0/G1 cell cycle arrest in breast cancer MCF-7 cells, acycloretinoic acid was about 100-fold less
potent as a ligand for RAR and its transactivation, compared to retinoic acid. It was not a ligand for
RXR. Since acycloretinoic acid had similar activity to lycopene in producing cell cycle arrest, these
investigators concluded that acycloretinoic acid was likely not an active metabolite of lycopene
(Ben-Dor et al. 2001). The minimal direct transcriptional activation seen with RAR still may be
due to polar lycopene oxidation products. These products are almost impossible to eliminate during
in vitro experiments, which may explain why lycopene is sometimes reported as directly involved
in RARE activation. However, the 100-fold weaker effect of acycloretinoic acid in RAR-mediated
actions discourages the pursuit of retinoid-like effects of lycopene or its oxidative metabolites.

μ

21.9.3 M ODULATION OF R EDOX -C ONTROLLED S IGNALING P ATHWAYS
Although the cellular concentrations of lycopene or its oxidation products may be too low to have
a general antioxidant or pro-oxidant effect on cells, there is sufi cient evidence of its in vivo effect
on the classical measures of oxidative stress to indicate that its participation in the redox state