Carotenoids as Modulators of Molecular Pathways Involved in Cell Proliferation and Apoptosis - Carotenoids: Physical, Chemical, and Biological Functions and Properties - page 474

Recently, fucoxanthin has been shown to inhibit the proliferation of human colon cancer cells by
a mechanism involving an up-regulation of p21WAF1/Cip1 (Das et al., 2005).
22.11 MODULATION OF APOPTOSIS-RELATED PROTEINS
Apoptosis helps to establish a natural balance between cell death and cell renewal in mature ani-
mals by destroying the excess, damaged, or abnormal cells. However, the balance between survival
and apoptosis often tips toward the former in cancer cells. In fact, the intricate network of apoptotic
signaling is often dysregulated in cancer cells. One example of this is the up-regulation of the anti-
apoptotic protein Bcl-2 in human colon cancer cells. The Bcl-2 protein family is important for the
regulation of apoptosis and it includes anti-apoptotic members such as Bcl-2 and Bcl-xl, as well as
the pro-apoptotic members such as Bax, Bak, Bad (Bcl-2/Bcl XL -antagonist, causing cell death), and
Bid. Their main site of action is believed to be the mitochondria, where they facilitate or impede the
release of cytochrome c.
Several studies show that carotenoids are able to act as apoptosis inducers by modulating dif-
ferent molecular pathways involved in the apoptotic process, as recently reviewed (Palozza et al.,
2004a).
22.11.1 B CL -2 F AMILY P ROTEINS
It has been demonstrated that b-carotene is able to decrease the expression of Bcl-2 and Bcl XL
in colon cancer cells (Palozza et al., 2001b) and to diminish that of Bcl-2 in HL-60 cells (Palozza
et al., 2002b). Such effects were strictly related to apoptosis induction and to ROS production by the
carotenoid. This i nding is particularly interesting in the light of the data supporting a role for Bcl-2
in an antioxidant pathway, whereby this protein prevents programmed cell death by decreasing for-
mation of reactive oxygen species and lipid peroxidation products (Kane et al., 1993).
In addition, recent data suggest that carotenoids modulate Bid (Palozza et al., 2006a; Prasad
et al., 2006), Bad (Liu et al., 2003), Bcl-xl (Prasad et al., 2006), and Bax (Palozza et al., 2004a)
expression in different experimental models. In particular, it has been recently shown that the
increase in Bax expression and in apoptosis induction caused by cigarette TAR was prevented by
the addition of b-carotene in RAT-1 i broblasts as well as in different tumor cell lines (Palozza
et al., 2004a). In addition, recently, it has been reported that lycopene can induce apoptosis of PC-3
cells, downregulating the expression of cyclin D1 and Bcl-2 and upregulating that of Bax (Wang
et al., 2007).
22.11.2 C ASPASE C ASCADE
The mechanism(s) of caspase cascade activation during b-carotene-induced apoptosis has been
recently investigated in tumor cells (Palozza et al., 2003a). b-carotene-induced apoptotic pathway
requires activation of caspase-3, which has been dei ned as a key player in apoptosis induced by
many stimuli and is also necessary for the nuclear changes associated with apoptosis, such as chro-
matin condensation. The carotenoid can initiate caspase-3 cascade mainly by interacting with a sig-
nal complex on cell membrane, which induces caspase-8 activation, and then by operating through
a non-receptor signaling pathway within cytoplasm, which induces caspase-9 activation (Palozza et
al., 2003a). How caspase-8 can be activated by b-carotene is not clear. The authors suggest differ-
ent hypotheses. It is possible that b-carotene activates TNF/Fas ligand system/receptor. Moreover,
it is known that ROS may be implicated in the activation of caspase-8 and the carotenoid has been
reported to act as a redox agent. Finally, the carotenoid may induce conformational changes of some
membrane-associated “death” receptors, resulting in the activation of caspase-8. A direct activation
of caspase-9 via caspase-8 by b-carotene has also been reported in tumor cells. The carotenoid