Carotenoids as Modulators of Molecular Pathways Involved in Cell Proliferation and Apoptosis - Carotenoids: Physical, Chemical, and Biological Functions and Properties - page 467

interleukin (IL)-1, lypopolysaccharide (LPS), phorbol myristate acetate, UV and ionizing radiation,
generated elevated levels of ROS, prompted speculation that ROS may function as common media-
tors of NF-kB activation.
We recently reported that b-carotene induced a signii cant increase in ROS production and/or in
oxidized glutathione content in HL-60 cells (Palozza et al., 2002b) as well as in colon adenocarci-
noma cells (Palozza et al., 2001a). These effects were always accompanied by a sustained elevation
of NF-kB and by a signii cant inhibition of cell growth (Palozza et al., 2003b). Interestingly, in all
cell lines studied, a-tocopherol and N -acetylcysteine inhibited the effects of b-carotene on cell
growth and apoptosis, and normalized the increased expression of c-myc induced by the carotenoid,
suggesting that a redox regulation of NF-kB induced by b-carotene may be involved in the growth-
inhibitory and pro-apoptotic effects of the carotenoid in tumor cells (Palozza et al., 2003b).
In addition, it has been recently reported that lycopene signii cantly inhibited MMP-9 levels
and the binding abilities of NF-kB and stimulatory protein 1 (Sp1) in the human hepatoma cell
line SK-Hep-1, suppressing the invasive ability of these cells. Such an effect was also accompa-
nied by a decrease in the expression of the insulin-like growth factor-1 receptor (IGF-1R) and
in the intracellular level of ROS (Huang et al., 2007). Moreover, it has been also reported that
combinations of vitamin D3 and dietary antioxidants, including b-carotene, may be useful in over-
coming the differentiation block present in acute promyelocytic HL-60 leukemia cells through a
mechanism involving a marked reduction in the nuclear content of NF-kB (Sokoloski et al., 1997).
Recent data suggest that carotenoid molecules may represent nontoxic agents for the control of
pro-inl ammatory genes through a mechanism involving NF-kB. In fact, lycopene prevented mac-
rophage activation induced by gliadin and IF-g through an inhibition of the activation of NF-kB,
interferon regulatory factor-1 and signal transducer and activator of transcription-1a and lowered
the levels of both nitric oxide synthase and cyclooxygenase-2 (COX-2) (De Stefano et al., 2007).
Similarly, astaxanthin (Lee et al., 2003) and b-carotene (Bai et al., 2005) inhibited the production
of inl ammatory mediators by blocking NF-kB activation in both LPS-stimulated RAW264.7 cells
and primary macrophages. A mechanism of inhibition of NF-kB by lycopene seems to be also
involved in the ability of the carotenoid to suppress the LPS-induced maturation of dendritic cells
(Kim et al., 2004).
22.3 MODULATION OF ACTIVATED PROTEIN-1 ACTIVATION PATHWAY
Activated protein-1 (AP-1) is another transcription factor that regulates the expression of several
genes that are involved in cell differentiation and proliferation. The functional activation of the AP-1
transcription complex is implicated in tumor promotion as well as in malignant transformation.
This complex consists of either homo- or heterodimers of the members of the jun and fos family of
proteins (Eferl and Wagner., 2003). This AP-1 mediated transcription of several target genes can
also be activated by a complex network of signaling pathways that involves external signals such as
growth factors, mitogen-activated protein kinases (MAPK), extracellular-signal regulated protein
kinases (ERK), and c-Jun N-terminal kinases (JNKs). Some of the target genes that are activated by
AP-1 transcription complex mirror those activated by NF-kB and include cyclin D1, Bcl-2, Bcl-xl,
VEGF, MMP, and urokinase-type plasminogen activator (uPA). Expression of genes such as MMP
and uPA especially promotes angiogenesis and invasive growth of cancer cells. Most importantly,
AP-1 can also promote the transition of tumor cells from an epithelial to mesenchymal morphology,
which is one of the early steps in tumor metastasis. These oncogenic properties of AP-1 are primar-
ily dictated by the dimer composition of the AP-1 family proteins, and their posttranscriptional and
translational modii cations.
Recent observations suggest that carotenoids may modulate the AP-1 activation process. It has
been recently reported in mammary tumor cell lines that b-carotene and its cleavage products were
able to decrease the activation of AP-1 (Tibaduiza et al., 2002). Moreover, lycopene was also shown
to downregulate AP-1 in mammary cancer cells (Karas et al., 2000). In addition, a pharmacological