Lycopene Oxidation, Uptake, and Activity in Human Prostate Cell Cultures - Carotenoids: Physical, Chemical, and Biological Functions and Properties - page 450

There are several alternative pathways associated with the balance between proliferation and
apoptosis that are affected by lycopene treatment, especially the insulin-like growth factor (IGF)
signaling pathway. Another is the possibility that lycopene or one of its breakdown products has
retinoid activity. Kotake-Nara et al. compared acyclo-retinoic acid, an in vitro oxidation product
of lycopene, to four actively researched anticarcinogenic retinoids. Acycloretinoic acid was found
to more actively reduce PC-3 and DU-145 cell viabilities (but not LNCaP) through apoptosis in
a medium already containing small amounts of natural retinoids. But study concentrations were
20 M, far above physiologically relevant lycopene concentrations, let alone the smaller concentra-

tion of one of its breakdown products. Acycloretinoic acid had a very low afi nity for the retinoid X
receptors (RXR) and retinoic acid receptors (RAR) receptors (Kotake-Nara et al. 2002).

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21.7 LYCOPENE AND THE INSULIN-LIKE GROWTH
FACTOR SIGNALING PATHWAY
The mechanism for lycopene's possible interference with IGF signaling has recently become a focus
for cell culture studies since lycopene has been shown to interfere with both IGF signaling and
androgen pathways in the normal and cancerous rat prostate glands (Herzog et al. 2005, Siler et al.
2004). Furthermore, elevated plasma concentrations of IGF-1 and the ratio IGF-1/IGFBP-3 (insulin-
like growth factor binding protein 3) are risk factors for prostate cancer (Li et al. 2003, Miyata et al.
2003, Mucci et al. 2001, Oliver et al. 2004) and there is an inverse association between plasma IGF-1
concentration and tomato intake (Gunnell et al. 2003, Mucci et al. 2001). It appears that lycopene
supplementation may increase IGF binding proteins but less so circulating levels of IGF-1 (Graydon
et al. 2007, Riso et al. 2006, Voskuil et al. 2008, Vrieling et al. 2007). However, these circulating lev-
els might be of liver origin and may not rel ect what is happening in various types of prostate cells.
The IGF pathway has been the focus of research for several different cancers and is associated
with mitogenesis and the down-regulation of apoptosis. It is composed of a number of components:
IGFs (secreted by not only liver cells but also by a number of other tissues), IGF binding proteins
(most of plasma IGF-1 is bound to IGFBP-3), and IGF receptors. In the prostate, stromal cells are
the principal secretors of IGF-1 with small amounts detectable in LNCaP and DU-145 cells. When
stromal PrSC cells are cocultured with either LNCaP or DU-145 cell, these cancer epithelial cells
are more proliferative, both in vitro and in vivo , and when PrSC cell IGF-1 secretion is blocked or
the IGF-1 receptor (IGF-IR) is blocked, cancer cell proliferation is decreased (Kawada et al. 2006).
Interestingly, a study of IGF-IR staining in normal and prostate cancer specimens showed that
IGF-IR was expressed in normal and prostate cancer epithelial cells but rarely in adjacent stromal
cells (Ryan et al. 2007). Therefore, IGF-1 is an important mediator of the stromal cell support of
epithelial cell carcinogenesis.
Table 21.3 summarizes the tissue culture studies that have explored the action of lycopene on the
IGF axis using prostate cells. Both Ivonov et al. (2007) and Kanagaraj et al. (2007) found detectable
IGF-1 in cell culture medium, presumably produced from their PC-3 epithelial cells, but lycopene
treatment (40-60

M) had no effect on IGF-1 concentrations. Both groups of investigators found
1.5- to 2-fold increases in IGFBP-3 in cells and the culture medium that corroborates the human stud-
ies, even though the lycopene doses used were much higher than could be achieved physiologically.
Both investigative groups also reported that when PC-3 cells were stimulated to increased growth by
IGF-1 exposure the lycopene decreased the IGF-1 stimulated IGF-IR expression (Table 21.3). Liu et
al. (2008) continued to explore the stromal, epithelial cell interactions of IGF signaling using DHT
(stimulator) and lycopene (inhibitor) as probes. They used the PrSC stromal cell lines or stromal
i broblasts (6S) (derived from a prostate cancer patient), which were cocultured with primary epithe-
lial cells (NPE) without the androgen receptor. Lycopene, at physiological concentrations, decreased
by 50% the sixfold induction of IGF-1 mRNA caused by DHT in PrSC stromal cells, but had no
effect on non-DHT-stimulated cells. The lycopene effect may be due to a reduction (60%-70%) in

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