Carotenoids as Modulators of Molecular Pathways Involved in Cell Proliferation and Apoptosis - Carotenoids: Physical, Chemical, and Biological Functions and Properties - page 475

increased the expression of the truncated form of Bid, which translocates to the mitochondria and
acts as a potent inducer of apoptosis, by releasing cytochrome c and activating caspase-9 (Palozza
et al., 2003a).
Moreover, a recent study also revealed that ROS generation led to the activation of caspase-2
during b-carotene-induced apoptosis in the human leukemic T cell line Molt 4. The apoptosis
progressed by simultaneous activation of caspase-8 and caspase-9, and a cross talk between these
initiator caspases was mediated by the pro-apoptotic protein Bid. Inhibition of caspases 2, 8, 9,
and 3 independently suppressed the caspase cascade. The cleavage of the anti-apoptotic protein
BclXL was found to be another important event during b-carotene-induced apoptosis, suggesting
the presence of an extensive feedback amplii cation loop in b-carotene-induced apoptosis (Prasad
et al., 2006).
22.11.3 M ITOCHONDRIAL P ROTEINS
The involvement of mitochondria in the pro-apoptotic effects of carotenoids has been clearly dem-
onstrated by the fact that b-carotene induces the release of cytochrome c from mitochondria and
alters the mitochondrial membrane potential (Dym) in different tumor cells (Palozza et al., 2003a).
Moreover, the highly polar xanthophyll neoxanthin has been reported to induce apoptosis in colon
cancer cells by a mechanism that involves its accumulation into the mitochondria and a consequent
loss of mitochondrial transmembrane potential and releas of cytochrome c and apoptosis-inducing
factor (Terasaki et al., 2007).
22.11.4 C YCLOOXYGENASE
Numerous preclinical studies point out the importance of regulation of cyclooxygenase-2 (COX-2)
expression in the prevention and, most importantly, in the treatment of several malignancies. This
enzyme is overexpressed in practically every premalignant and malignant conditions involving
colon, liver, pancreas, breast, lung, bladder, skin, stomach, head and neck and esophagus cancers
(Eberhart et al., 1994). Overexpression of this enzyme is a consequence of a deregulation of tran-
scriptional and/or posttranscriptional control. Several growth factors, cytokines, oncogenes, tumor
promoters stimulate COX-2 transcription. Expression of COX-2 is increased in HER2/neu express-
ing breast carcinomas owing to enhanced Ras signaling. Depending upon the stimulus and the cell
type, different transcription factors, including AP-1, NF-IL-6, NF-kB, can stimulate COX-2 tran-
scription. One of the possible mechanisms by which COX-2 can induce tumorigenesis is through
its ability to act as an anti-apoptotic gene. A recent study in our laboratory shows that b-carotene is
able to downregulate the expression of COX-2 in colon cancer cells and such an effect was accom-
panied by apoptosis induction (Palozza et al., 2005a). This observation is particularly interesting in
view of the fact that COX-2 expression is regulated by PPARg and PPAR receptors have been sug-
gested to be modulated by carotenoids (Sharoni et al., 2002).
22.12 MODULATION OF DIFFERENTIATION-RELATED PROTEINS
The induction of differentiation may be an effective mechanism for chemoprevention of chronic
diseases. It has been reported that lycopene alone induced differentiation of HL-60 promyelocytic
leukemia cells (Amir et al., 1999). A similar effect was also observed for other carotenoids, includ-
ing b-carotene and lutein (Liu et al., 1997; Sokoloski et al.,1997).
The differentiation effect of lycopene was associated with elevated expression of several
differentiation-related proteins, such as cell surface antigen (CD14), oxygen burst oxidase
and chemotactic peptide receptors (Amir et al., 1999). Recently, it has also been reported that
lycopene was also able to stimulate the differentiation marker alkaline phosphatase activity in