Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
ReviewCell signaling pathways altered by natural chemopreventive agents
Introduction
It has been known that most human cancers are induced by environmental factors including chemical, radioactive and biological factors that exist in our living environment. There are significant differences in the cancer incidence and mortality among ethnic groups, who have different lifestyles and have been exposed to different environmental factors [1]. It has been estimated that more than two-thirds of human cancers could be prevented by modification of lifestyle including dietary modification [2]. The consumption of fruits, soybean and vegetables has been associated with reduced risk of several types of cancers [3], [4], [5]. The experimental in vitro and in vivo studies have demonstrated that some dietary components such as isoflavones, indole-3-carbinol (I3C), 3,3′-diindolylmethane (DIM), curcumin, (−)-epigallocatechin-3-gallate (EGCG), apigenin, have inhibitory effects on human cancers [6], [7], [8], [9], [10], [11], [12], [13] suggesting that they may serve as chemopreventive agents.
The dietary components as chemopreventive agents have received much attention among the public and the medical community. Soy isoflavones including genistein, daidzein, and glycitein, mainly derived from soybean have been found to inhibit cancer growth in vivo and in vitro [14], [15], [16]. I3C and its in vivo dimeric product DIM, produced from naturally occurring glucosinolates in the family Cruciferae, have shown the inhibition of cancer cell growth through the modulation of genes that are related to the control of cell proliferation, cell cycle, apoptosis, signal transduction, oncogenesis, and transcription regulation [8], [9]. Curcumin, a natural compound present in turmeric and possessing both anti-inflammatory and antioxidant effects, has been studied as a chemopreventive agent in several cancer models [11], [17]. Beneficial effects attributed to green tea, such as its anticancer and antioxidant properties, are believed to be mainly mediated by EGCG [4], [18]. Apigenin, one of the flavonoids, is widely distributed in many fruits and vegetables, and has been shown to possess anti-inflammatory and anticancer effects [19], [20]. It is becoming clear that these dietary components exert their pleiotropic effects on cancer cells, affecting cell survival and physiological behaviors. However, the precise molecular mechanisms of actions of these components have not been fully elucidated, although the data from published literature does indicate that these components regulate transcription, translation and activation of the molecules in the cell signal transduction pathways. Among the cell signaling pathways, NF-κB, Akt, MAPK, p53, AR, and ER pathways are more important signaling pathways related to cancer development and progression. This article reviews current studies regarding the effects of natural chemopreventive agents on these cancer-related cell signaling pathways and provides comprehensive knowledge of the biological and molecular roles of chemopreventive agents in cancer cells.
Section snippets
Effects of chemopreventive agents on NF-κB
It has been well accepted that nuclear factor-κB (NF-κB) signaling pathway plays important roles in the control of cell growth, apoptosis, inflammation, stress response, and many other physiological processes [21], [22], [23], [24], [25]. There are several important molecules such as NF-κB, IκB, IKK, within NF-κB signaling pathway (Fig. 1). However, NF-κB is the key protein in the pathway, and has been described as a major culprit and a therapeutic target in cancer [26], [27], [28], [29]. The
Effects of chemopreventive agents on Akt
Akt plays critical roles in mammalian cell survival signaling and has been shown to be activated in various cancers [48], [49]. It has been known that Akt is activated by phospholipid binding and phosphorylation at Thr308 by PDK1 or at Ser473 by PDK2 [50]. Activated Akt functions to promote cell survival by inhibiting apoptosis through inactivation of several pro-apoptotic factors including Bad, Forkhead transcription factors, and caspase-9 [51], [52], [53]. Recent studies have also shown that
Effects of chemopreventive agents on MAPK
In addition to NF-κB and Akt pathways, MAPK has received increasing attention as a target molecule for cancer prevention and therapy. It has been reported that activation of the MAPK pathways may cause the induction of phase II detoxifying enzymes, and inhibition of MAPK pathways may inhibit AP-1-mediated gene expression [65]. MAPK pathway consists of a three-tiered kinase core where a MAP3K activates a MAP2K that activates a MAPK (ERK, JNK, and p38), resulting in the activation of NF-κB, cell
Effects of chemopreventive agents on p53
p53 is a tumor suppressor and transcription factor. It is a critical regulator in many cellular processes including cell signal transduction, cellular response to DNA-damage, genomic stability, cell cycle control, and apoptosis. As a tumor suppressor, functional p53 activates the transcription of downstream genes such as p21WAF1 and Bax to induce the apoptotic process, inhibiting the growth of DNA damaged cells or cancer cells [74], [75], [76]. The status of p53 is thought to be an important
Effects of chemopreventive agents on AR
It has been found that androgen receptor (AR) signaling pathway plays important roles in the carcinogenesis and cancer progression through regulation of transcription of androgen-responsive genes [84] (Fig. 2). Several chemopreventive agents including genistein, I3C, DIM, and curcumin, have been found to regulate the molecules in AR signaling pathway when they were used to inhibit growth of cancer cells.
Prostate specific antigen (PSA), one of the androgen-responsive genes, is a clinically
Effects of chemopreventive agents on ER
Many environmental chemicals have been found to be estrogenic and have been shown to stimulate the growth of ER-positive human breast cancer cells [91], [92]. Because it is difficult to avoid human exposure to environmental estrogens, it is important to develop dietary strategies to prevent the stimulated growth of breast tumors by environmental estrogens. Isoflavone has a close similarity in structure to estrogen, and has been known as phytoestrogen. Because of the structural similarity to
Summary and perspectives
The data from in vivo human and animal studies and in vitro experiments clearly indicate that natural chemopreventive agents exert their inhibitory effects on carcinogenesis and tumor progression. These effects have been believed to be mediated through the regulation of cell signaling pathways including NF-κB, Akt, MAPK, p53, AR, and ER pathways. As we discussed earlier, there are cross-talks between these pathways. Natural chemopreventive agents could exert their effects on these pathways
Acknowledgments
The authors’ work cited in this review was funded by grants from the National Cancer Institute, NIH (5R01CA101870-02, 1R01CA108535-01, and 5R01CA083695-04 awarded to FHS) and a grant from the Department of Defense (DOD Prostate Cancer Research Program DAMD17-03-1-0042 awarded to FHS).
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