ReviewCellular signaling perturbation by natural products
Introduction
Cellular signaling is a complex signal communication network which controls basic biological activities of cells and coordinates cell actions. It has been known that signaling cascades are typically composed of three-dimensional pathways of proteins which regulate each other in the specific location of cells [1]. Because of the complex transduction of cell signaling, cancer cells always show the alterations in multiple cellular signaling pathways. Perhaps, this is the reason why the specific inhibitors that target only one pathway, most often, failed in cancer treatment. In cancer cells, the cellular signaling pathways which control cell cycle and apoptosis are almost always malfunctioning, leading to the uncontrolled cell proliferation and the formation of tumor. Several cellular signaling pathways including NF-κB, Akt, MAPK, Wnt, Notch, p53, AR, and ER, etc, have been known to control cell proliferation and apoptosis. Importantly, all of these signaling pathways have been found malfunctioning in cancer cells, resulting in cancer cell proliferation and inhibition of apoptosis [2], [3], [4], [5], [6]. Therefore, it is important to design a strategy that could simultaneously target multiple cellular signaling pathways so that cancer cells could get killed effectively.
In recent years, dietary compounds (natural agents) harvested from the bounties of nature have received much attention, primarily because epidemiological studies have shown that the consumption of fruits, soybean and vegetables is associated with reduced risk of several types of cancers [7], [8], [9]. The natural products including isoflavone genistein, indole-3-carbinol (I3C), 3,3'-diindolylmethane (DIM), curcumin, (−)-epigallocatechin-3-gallate (EGCG), resveratrol, lycopene, etc, have been recognized as cancer chemopreventive agents because of their anti-carcinogenic activity [10], [11]. The in vitro and in vivo studies have demonstrated that these natural products (natural agents) have inhibitory effects on various human and animal cancers [12], [13], [14], [15], [16], [17], [18], [19]; therefore, many investigators have focused on elucidating the molecular mechanisms and identifying the targets of action of these natural products.
Soy isoflavones such as genistein, daidzein, and glycitein are mainly derived from soybean. Genistein has been found to inhibit cancer cell growth in vivo and in vitro [20], [21], [22]. I3C and its in vivo dimeric product DIM are produced from naturally occurring glucosinolates found in the family Cruciferae. I3C and DIM have shown inhibitory effects on 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 [14], [15]. Curcumin is a natural compound present in turmeric and has been known to possess both anti-inflammatory and antioxidant effects. However, it has also been studied as a cancer chemopreventive agent in several cancer models [17], [23]. EGCG that exists in green tea has shown antioxidant and anticancer activities in several types of cancer [8], [24]. Resveratrol (3,5,4′-trihydroxystilbene) is a phytoalexin present in a wide variety of plant species including grapes, mulberries, and peanuts. Experimental studies have shown that resveratrol inhibits the growth of various cancer cells and induces apoptotic cell death [25], [26]. Lycopene rich in tomatoes has been shown to inhibit cell growth in various cancer cells with regulation of cell cycle-related genes [27], [28]. Due to emerging evidence from increasing number of investigations on these natural products, it is becoming clear that these natural products exert their pleiotropic effects on cancer cells through targeting multiple cellular signaling pathways including NF-κB, Akt, MAPK, Wnt, Notch, p53, AR, and ER pathways, suggesting that these natural products could be useful either alone or in combination with conventional therapeutics for the prevention of tumor progression and/or treatment of human malignancies. The roles of many of these signaling pathways are succinctly presented below in this article.
Section snippets
Malfunctioning of cellular signaling in cancer cells
In cancer cells, the altered proteins produced from the mutations or defects of genes impact the way that cell signals communicate with each other. The important cellular signaling pathways which are known to malfunction in cancer cells include NF–κB, Akt, MAPK, Wnt, Notch, p53, AR, ER, etc. among many others.
It is now 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
Isoflavone
Our laboratory has investigated the effects of isoflavone genistein on multiple signaling pathways. Because NF-κB is one of the most important pathways deregulated in cancer cells, we examined NF-κB DNA-binding activity in genistein treated prostate cancer cells by electrophoresis mobility shift assay (EMSA) [62]. We found that genistein significantly inhibited the NF-κB DNA-binding activity in prostate cancer cells. Furthermore, genistein pre-treatment abrogated the activation of NF-κB
Summary and perspectives
The data from in vivo human and animal studies and in vitro experiments clearly indicate that natural products (natural agents) including isoflavones, I3C, DIM, curcumin, EGCG, resveratrol, and lycopene exert their inhibitory effects on carcinogenesis and cancer progression. These effects have been believed to be mediated through the regulation of multiple cell signaling pathways including NF-κB, Akt, MAPK, Wnt, Notch, p53, AR, and ER pathways among others. Because of the complex communication
Acknowledgements
The authors' work cited in this review was funded by grants from the National Cancer Institute, NIH (5R01CA108535, 5R01CA083695, and 5R01CA101870 awarded to FHS).
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2021, Pharmacology and TherapeuticsCitation Excerpt :This raised phosphorylation levels of β-catenin and suppressed the growth of prostate cancer (Parket al., 2005; Su, Simmen, Xiao, & Simmen, 2007). Genistein also reduced Wnt-1-induced proliferation and expression of cyclin D1 and c-Myc in prostate cancer cells (Li et al., 2008; Sarkar, Li, Wang, & Kong, 2009). The anti-inflammatory action of genistein was evaluated against breast cancer cells by Pons and team (Pons et al., 2019).