Oxidative Metabolites of Lycopene and Their Biological Functions - Carotenoids: Physical, Chemical, and Biological Functions and Properties - page 427

20.4.5 I NTERFERENCE WITH G ROWTH F ACTORS
IGFs (IGF-1 and IGF-2) are mitogens that play a central role in the regulation of cellular prolifera-
tion, differentiation, and apoptosis (Yu and Rohan 2000). By binding to membrane IGF-1 receptors,
IGFs activate intracellular phosphatidylinositol 3 -kinase/Akt/protein kinase B and Ras/Raf/MAPK

pathways, which regulate various biological processes, such as cell cycle progression, survival, and
transformation (Clemmons et al. 1995). IGFs are sequestered in circulation by a family of binding
proteins (IGFBP1-IGFBP6), which regulate the availability of IGFs to bind with IGF receptors
(Clemmons et al. 1995). The disruption of normal IGF signaling, leading to hyperproliferation and
survival signal expression, has been implicated in the development of several tumor types (Jerome
et al. 2003). Recent epidemiological studies provide supportive evidence that lycopene may have a
chemopreventive effect against a broad range of epithelial cancers, particularly prostate, breast, col-
orectal, and lung cancers (Arab et al. 2001, Clinton et al. 1996, Giovannucci 1999a,b, 2002). Sharoni
and colleagues provided a potential mechanism whereby lycopene interfered with IGF-I stimulated
cell growth (Karas et al. 1997, 2000, Levy et al. 1995). They showed that IGF-I stimulated cell
growth, as well as DNA binding activity of the AP-1 transcription factor, were reduced by the
physiological concentrations of lycopene in endometrial, mammary (MCF-7), and lung (NCI-H226)
cancer cell lines. Lycopene has been shown to inhibit IGF-1 stimulated insulin receptor substrate
1 phosphorylation and cyclin D1 expression, block IGF-1 stimulated cell cycle progression (Karas
et al. 2000, Nahum et al. 2006), and increase membrane-associated IGFBPs (Karas et al. 1997,
2000). Consistent with previous in vitro i ndings, recent epidemiological studies demonstrated that
the higher dietary intake of lycopene has been associated with the lower circulating levels of IGF-1
(Mucci et al. 2001) and the higher levels of IGFBPs (Holmes et al. 2002, Vrieling et al. 2007).
We have examined the effect of lycopene on the prevention of IGF signaling in cigarette smoke-
related lung carcinogenesis in the ferret model (Liu et al. 2003). We found that plasma IGF-1 levels
were not affected by cigarette smoke exposure or lycopene supplementation. However, IGFBP-3
levels were increased by lycopene supplementation and decreased by smoke exposure. Interestingly,
lycopene increased plasma IGFBP-3 regardless of smoke exposure status. Increased plasma
IGFBP-3 was associated with the inhibition of cigarette smoke-induced lung squamous metaplasia,
decreased proliferating cell nuclear antigen, phosphorylated BAD levels, and cleaved caspase 3
suggesting the inhibition of cell proliferation and the induction of apoptosis (Liu et al. 2003). These
results, along with others, suggest that the interference of IGF-1 signaling may be an important
mechanism by which lycopene exerts its anticancer activity. However, whether intact lycopene or its
metabolites are responsible for the observed effects on IGF-1 signaling remains unknown. We have
recently provided evidence that lycopene metabolites may be partly responsible. Treatment with
apo-10

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-lycopenoic acid (5-20 mM) resulted in a dose-dependent increase in IGFBP-3 mRNA levels
in THLE-2 human liver cells. Similar concentrations of retinoic acid, lycopene, and ACR showed
no signii cant effect on the induction of IGFBP-3 mRNA levels (unpublished results). Research into
this area is going on in this laboratory.

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20.4.6 C ELL P ROLIFERATION AND A POPTOSIS
The growth inhibitory effect of lycopene was i rst demonstrated by Levy et al., who showed that
lycopene is a stronger cell growth inhibitor than b-carotene (Levy et al. 1995). This growth inhibi-
tory effect was further observed in several cell lines, including breast cancer (Levy et al. 1995,
Nahum et al. 2001), prostate cancer (Levy et al. 1995), lung cancer (Levy et al. 1995), colon can-
cer (Salman et al. 2007), and oral cavity cancer cells (Livny et al. 2002), as well as normal pros-
tate epithelial cells (Obermuller-Jevic et al. 2003). The growth inhibition of lycopene on MCF-7
breast cancer cells was associated with a decreased G 1 -S cell cycle progression, a decreased cyclin
D1 expression, and the stabilization of p27 in the cyclin E-CDK complex (Nahum et al. 2001,
2006). In addition to cell-proliferation inhibition, the growth inhibitory effect of lycopene may