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Polyphenols as Antitumor Agents Targeting Key Players in Cancer-Driving Signaling Pathways - PubMed

  • ️Fri Jan 01 2021

Review

Polyphenols as Antitumor Agents Targeting Key Players in Cancer-Driving Signaling Pathways

Manuel Humberto Cháirez-Ramírez et al. Front Pharmacol. 2021.

Abstract

Polyphenols constitute an important group of natural products that are traditionally associated with a wide range of bioactivities. These are usually found in low concentrations in natural products and are now available in nutraceuticals or dietary supplements. A group of polyphenols that include apigenin, quercetin, curcumin, resveratrol, EGCG, and kaempferol have been shown to regulate signaling pathways that are central for cancer development, progression, and metastasis. Here, we describe novel mechanistic insights on the effect of this group of polyphenols on key elements of the signaling pathways impacting cancer. We describe the protein modifications induced by these polyphenols and their effect on the central elements of several signaling pathways including PI3K, Akt, mTOR, RAS, and MAPK and particularly those affecting the tumor suppressor p53 protein. Modifications of p53 induced by these polyphenols regulate p53 gene expression and protein levels and posttranslational modifications such as phosphorylation, acetylation, and ubiquitination that influence stability, subcellular location, activation of new transcriptional targets, and the role of p53 in response to DNA damage, apoptosis control, cell- cycle regulation, senescence, and cell fate. Thus, deep understanding of the effects that polyphenols have on these key players in cancer-driving signaling pathways will certainly lead to better designed targeted therapies, with less toxicity for cancer treatment. The scope of this review centers on the regulation of key elements of cancer signaling pathways by the most studied polyphenols and highlights the importance of a profound understanding of these regulations in order to improve cancer treatment and control with natural products.

Keywords: MAPK; PI3K-AKT pathway; RAS; cancer; p53; polyphenols; signaling pathways.

Copyright © 2021 Cháirez-Ramírez, de la Cruz-López and García-Carrancá.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1

General classification of polyphenols, representative compounds by group, and their associated rich food sources.

FIGURE 2
FIGURE 2

Overview of p53 domain structure and posttranslational modifications induced by polyphenols. Principal sites where polyphenols induce p53 posttranslational modifications (phosphorylation, acetylation, methylation, or ubiquitination) are plotted. TAD, transactivation domain; PRD, proline-rich domain; DBD, DNA-binding domain; TD, tetramerization domain; CRD, C-terminal regulatory domain.

FIGURE 3
FIGURE 3

Potential sites of inhibitory actions of polyphenols in MAPK signaling pathways. ERK, extracellular signal-related kinases; JNK, c-Jun amino-terminal kinases; p38, p38 mitogen-activated protein kinase.

FIGURE 4
FIGURE 4

The inhibition of the PI3K/Akt/mTOR pathway by polyphenols in cancer. The phosphoinositide 3-kinase-AKT-mammalian target of rapamycin (PI3K/Akt/mTOR) pathway is hyperactivated in several cancers and is important in terms of tumor cell growth and survival. Activation of RTK, such as insulin-like growth factor-1 receptor (IGFR), by growth factors such as insulin, can initiate activation of intracellular pathways. Akt is phosphorylated downstream of PI3K with various effects, including the activation of mTOR. mTOR phosphorylates p70S6K and 4E-binding protein 1 (4EBP-1), which then leads to an increased translation of mRNA and cell growth. Polyphenols act by inhibiting this pathway by means of decreasing the phosphorylation of several protein kinases that are part of this signaling pathway. The green arrows indicate the activation of the pathway, while the red arrows indicate the inhibition of the pathway using different polyphenols.

FIGURE 5
FIGURE 5

p53 Stabilization by curcumin and synergy with routine therapy for the treatment of cervical cancer. Curcumin activates the Kelch-like ECH-associated protein 1-nuclear factor (erythroid-derived 2)-like 2 (Keap1/Nrf2) pathway, leading to an increase in the levels of NAD(P)H:quinone oxidoreductase 1 (NQO1). NQO1 binds to p53, promoting the loss of the interaction between p53 and E6AP, a negative regulator, promoting p53 stabilization in cancer cells with wild-type p53, such as cervical cancer cells. Moreover, a promising area of study is that of evaluating the synergistic effect of curcumin with routine chemotherapy, thus procuring a better response to treatment and fewer adverse effects.

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