Lycopene Oxidation, Uptake, and Activity in Human Prostate Cell Cultures - Carotenoids: Physical, Chemical, and Biological Functions and Properties - page 454

membranes and even extracellular matrix by the up-regulation of a system of MMPs via the
urokinase plasminogen activator system (activator + receptor + inhibitor). The up-regulation of the
receptor, urokinase plasminogen activated receptor (uPAR), has been shown to enhance invasion
and prostate cancer cell growth (Festuccia et al. 1998). Forbes et al. explored the effect of lycopene
to prevent invasion of a multipass bone metastatic prostate cell line (PC-3MM2) through a transwell
polycarbonate membrane coated with a Matrigel basement membrane matrix. Lycopene treatment
at the physiological dose of 1.0 M caused a doubling of the cells that invaded the matrix and an

increased expression of the uPAR without increasing the activator (uPA) and the inhibitor (PAI-1).
Lycopene had no effect on uPAR, uPA, or PAI-1 in regular PC-3 cells (Forbes et al. 2003) indicat-
ing that as transformation proceeds the mechanisms affected by lycopene may be lost, while other
processes may come to the fore that may be enhanced by the presence of lycopene. Since this paper
has appeared, clinicians have been concerned over the risk of lycopene supplementation for patients
with advanced metastatic prostate cancer (Ablin 2005). However, Huang et al. used highly invasive
liver SK-Hep-1 cells in the polycarbonate transwell matrigel system and found that lycopene sup-
pressed invasion, but this suppression was sensitive to lycopene concentration. Five

μ

μ M of lycopene

suppressed invasion by 81%-91% but higher concentrations were less suppressive. -carotene also

suppressed cell migration, but not invasion, and was far less effective than lycopene. The protein
nm23-H1 has been identii ed as an important suppressor of functions that are necessary for metas-
tasis. Lycopene treatment at 2.5 and 5

β

M concentrations increased nm23-H1 protein level by 220%
and its mRNA by 153%. Higher levels of lycopene reduced its expression (Huang et al. 2005).
Kozuki et al. also found that lycopene, as well as other carotenoids, inhibited hepatoma AH109A
from invading mesothelial cell membranes in coculture, and from the i gures presented in their
paper, it appeared that lycopene suppressed the invasion at a lower concentration (2.5

μ

μ M) than

other carotenoids (Kozuki et al. 2000).
In summary, lycopene must have some specii c effect on unknown cellular processes that control
the modulation of multiple pathways. General properties, such as antioxidation or pro-oxidation,
are unlikely to explain these effects. Since the activation, silencing or loss of pathway control is
different for each cell type and its degree of transformation, we do not have enough information to
predict whether lycopene may be benei cial or detrimental under different circumstances in various
prostate cell lines and in the different stages of prostate cancer.

21.9 IS THERE A CENTRAL MECHANISM FOR LYCOPENE ACTION?
The promise of cell culture studies is the elucidation of the mechanism(s) by which lycopene might
act to prevent the initiation, the promotion, or the progression of prostate cancer. Can the studies
performed, so far, point to these mechanisms? Wertz et al. suggested six possible modes of action for
lycopene in prostate health promotion as (1) antioxidant function, (2) the direct inhibition of cell cycle
progression, (3) the direct initiation of apoptosis, possibly by lycopene oxidation products, (4) the inhi-
bition of IGF-1 signal transduction, (5) the suppression of inl ammation, especially modulated by IL-6,
and (6) the inhibition of androgen activation and signaling (Wertz et al. 2004). The cell culture studies
have corroborated animal and human circumstantial evidences for most of these functions. Lycopene,
often at physiologically relevant concentrations, interferes with cell cycle and proliferation via cyclin
D 1 down-regulation. But is the concomitant increase in apoptosis, often seen in the same studies, an
independent effect? Several studies have found an up-regulation of IGFBP-3 and a smaller decrease
in IGF-1 output, especially from the stromal cells underlying the epithelial cells. Epithelial cells seem
to undergo the most radical neoplastic transformations. Interference suggested in androgen signaling
by lycopene may not be directly testable in cell culture and aside from determining lycopene effects
on androgen dependent- and independent-prostate cancer cell lines or observing lycopene effects with
and without DHT. The improvement of gap-junction communication via the increased synthesis of
Connexin 43 in prostate cancer cells by lycopene appears to be a completely different mode of action
and may or may not be connected with pathways that control cell invasion.