Advances in Understanding Renin–Angiotensin System-Mediated Anti-Tumor Activity of Natural Polyphenols

Figures

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  Figure 1. Schematic of the renin–angiotensin system (RAS) dual-axis and its association with tumor progression. Component definitions: AGT (angiotensinogen): RAS precursor, cleaved by renin to form AngI. Renin: catalyzes AGT → AngI; upregulated in renal cell carcinoma [4,5]. ACE (angiotensin-converting enzyme): catalyzes AngI → AngII (pro-tumor axis); overexpressed in gastric cancer [45]. ACE2 (angiotensin-converting enzyme 2): catalyzes AngII → Ang(1-7) (anti-tumor axis); downregulated in gallbladder cancer [52]. AngII (angiotensin II): binds AT1R (pro-tumor: proliferation/angiogenesis [42]) or AT2R (context-dependent [45,54]). Ang(1-7): binds MasR (anti-tumor: inhibits metastasis [51]). AT1R (AngII type 1 receptor): pro-tumor; high expression correlates with poor colorectal cancer survival [44]. AT2R (AngII type 2 receptor): anti-tumor in non-inflamed tissues; pro-tumor under H. pylori infection [45,54]. MasR (Mas receptor): mediates Ang(1-7)’s anti-angiogenic effects [50]. Symbol meanings: → (activation); ⊣ (inhibition); orange (pro-tumor axis: ACE/AngII/AT1R); green (anti-tumor axis: ACE2/Ang(1-7)/MasR/AT2R); * organize/microenvironment specificity, may be because of inflammation in…

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  Figure 2. Structural characteristics of flavonoid and non-flavonoid polyphenols. (A–E) Flavonoid polyphenols (C6-C3-C6 benzopyran ring framework). (A) Cyanidin (anthocyanin): contains multiple hydroxyl groups (-OH) on the B-ring, which enhance its affinity for ACE and AT1R [78]. (B) Epicatechin (flavanol): the 3′-OH group on the B-ring contributes to its inhibitory effect on renin activity [40]. (C) Quercetin (flavonol): the C3-OH and C5-OH groups are critical for modifying thiol-containing transmembrane proteins (e.g., A disintegrin and metalloproteinase 17, (ADAM17)) [79]. (D) Hesperetin (flavanone): lacks a C2-C3 double bond, improving its metabolic stability in vivo [68]. (E) Puerarin (isoflavone): the isoflavone skeleton structure enables it to suppress renal AGT expression via antioxidant activity [80]. (F–I) Non-flavonoid polyphenols. (F) Hydroxybenzoic acid (phenolic acid): the carboxyl group (-COOH) can form hydrogen bonds with the active site of ACE, enhancing inhibitory activity [81]. (G) Resveratrol (stilbene): the trans-stilbene structure is essential for upregulating ACE2 expression via the Sirtuin 1 pathway [82]. (H) Sesame lignans (lignan): the diphenylpropane skeleton…

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  Figure 3. Schematic of polyphenols inhibiting pro-tumor signaling cascades by regulating RAS dual-axis balance. Polyphenols: the central regulatory molecule (e.g., EGCG, resveratrol), which inhibits the pro-tumor axis and activates the anti-tumor axis [58,90]. RAS dual-axis: pro-tumor axis (ACE/AngII/AT1R), activates downstream pathways including NOX (inducing oxidative stress and inflammation) and Wnt (promoting angiogenesis and metastasis) [95,97]. Anti-tumor axis (ACE2/Ang(1-7)/AT2R): inhibits downstream pro-tumor pathways such as MAPK (reducing cell proliferation) and PI3K/ERK (inducing cell death) [51,99]. Tumor microenvironment indicates the comprehensive regulatory effect of polyphenols on the tumor microenvironment (e.g., reducing pro-inflammatory cytokines) [39].

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  Figure 4. Schematic of polyphenols regulating RAS by modifying thiol-containing transmembrane proteins. Polyphenols rapidly bind to cell surfaces and accumulate within 120 s [58,90]. Thiol-containing transmembrane proteins: (1) ADAM17: its phosphorylation is inhibited by polyphenols (e.g., rosmarinic acid), reducing ACE2 shedding and AT1R expression [79,103]. (2) Integrins (e.g., α2β1): polyphenols (e.g., carnosic acid) reduce their expression, decreasing ACE and AT1R levels and inhibiting AKT/ERK pathway activation [105,110]. RAS components: ACE, AT1R (pro-tumor), ACE2, AT2R, Ang(1-7), and MasR (anti-tumor), whose expression or activity is regulated by modified transmembrane proteins [107]. The dotted lines in the figure indicate that polyphenols may also bind to other membrane proteins containing sulfhydryl groups and thereby regulate the expression of RAS.