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. 2019 Mar 1;20(5):1062. doi: 10.3390/ijms20051062

Table 3.

Molecular targets for the dietary polyphenols in prostate cancer.

Cellular Effect Polyphenol Molecular Target Cell Line/
Animal Model/
Clinical Trial		 References
Antioxidant effect Quercetin ↓ROS ↑SOD, ↑CAT, ↑GPx, ↑GSR Sprague‒Dawley rats [100]
Genistein ↑GPx LNCaP, PC-3 cell lines [99]
EGGC ↑SOD DU-145 cell line [101,102]
Pro-oxidant effect Apigenin ↑ROS 22Rv1 cell line [150]
Quercetin ↑ROS DU-145 cell line [97]
Androgen and estrogen receptors Quercetin ↓AR LNCaP cell line [106,195,196]
Genistein ↓AR (high doses of genistein) in correlation with ↓HSP90 Sprague‒Dawley rats
LNCaP cell line		 [66,107,197,198]
↓ERα ‒-Dawley rats [198]
↑AR (physiological doses of genistein) PC-3 cells transfected with T877A-AR [107]
Resveratrol ↓AR LNCaP cell line
HeLa cells transfected with human AR		 [108,109,110,111,112]
↓ERα PC-3 cell line [108]
EGCG ↓AR, ↓ mRNA for AR 22Rv1 tumor xenograft in nude mice [113]
Growth factors and cytokines receptors Apigenin ↓IGF-1 TRAMP mice [117]
Resveratrol ↓EGFR, ↓HER2 LNCaP, C4-2 cell lines [118]
Curcumin ↓CXCL-1, -2
↓EGFR (Tyr 845, Tyr 1068)		 PC-3 cell line [119,120]
EGCG ↓c-Met/HGF (Tyr1234/1235) DU-145 cell line [121]
Signal transduction Apigenin ↓PI3K, ↓p-Akt (Ser473, Thr308), ↓ERK1/2,
↓p-FoxO (Ser253), ↓NF-κB		 22Rv1
TRAMP mice
Prostate CSC (CD44+) isolated from PC-3 cells		 [82,117,125,150]
CAPE ↓ERK1/2,
↓p-Akt (Ser473),
↓p-mTOR (Ser2448, Ser24981),
↓p-GSK3α (Ser21),
↓p-GSK3β (Ser9),
↓p-PDK1 (Ser241)		 LNCap, DU-145,
PC-3 cell lines		 [130,131]
Curcumin ↓NF-κB
↓p-PI3K, ↓p-Akt (Ser 473, Thr 208),
↓p-IκB		 LNCaP, PC-3 cell lines [119,120,132]
Gallic acid ↓SOS, ↓GRB2, ↓PKC, ↓NF-κB, ↓JNK, ↓ERK1/2, ↓p38-MAPK, ↓p-Akt LNCaP, DU-145,
PC-3 cell lines		 [95]
Gingerol ↓MRP1 PC-3 cell line [134]
EGCG ↓NF-κB, ↓ERK1/2, ↓p-Akt DU-145 cell line [90,121]
Resveratrol ↓PI3K, ↓Akt,
↓GSK-3, ↑PTEN		 LNCaP, PC-3 cell lines
TRAMP mice		 [108,118]
Cell cycle Apigenin ↓cyclin D1
Arrest in G0/G1 or G2/M phase		 LNCaP, PC-3 cell lines
TRAMP mice		 [125,139]
CAPE ↓cyclin D1
↓cyclin E		 PC-3 cell line [130]
Gallic acid G2/M arrest
↓cdc25
↑CHK1, CHK2		 LNCaP, DU-145, PC-3 cell lines [95]
Gingerol ↓cyclin D1, ↓cyclin E ↓CDK4 Normal prostate epithelial cells (PrEC)
PCa cell lines: LNCaP, DU-145, PC-3, C4-2, C4-2B		 [71]
EGCG G0/G1 arrest or G2/M arrest—cell-line-dependent LNCaP, DU-145, PC-3 cell lines [144]
Quercetin G0/G1 arrest
↓CDK2, ↓cyclin E ↓cyclin D		 PC-3 cell lines [68]
Apoptosis Apigenin ↑caspase-3, -8
↓ΔΨm
↑cytochrome c
↓Bcl-2, ↓Bcl-XL
↑Bax
↑TRAIL, ↑DG5		 22Rv1,
PC-3 (p53-/-),
PC-3(p53+/+) cell lines
Prostate CSC (CD44+) isolated from PC-3 cells 		[82,150,151]
Gallic acid ↑cytochrome c
↑caspase-3, -8, -9		 LNCaP cell line [96]
Gingerol ↑caspase-3, ↑PARP
↓Bcl-2		 Normal prostate epithelial cells (PrEC)
PCa cell lines: LNCaP, DU-145, PC-3, C4-2, C4-2B		 [71]
EGCG ↓Bcl-2, ↑Bax
↑caspase-3, -8, -9
↑PARP
↑CHOP/GADD153		 LNCaP, DU-145, PC-3 cell lines [144,154]
Quercetin ↓Bcl-2, ↑Bax
↑caspase-3, -8, -9
↑ATF
↑GRP78
↑GADD153		 PC-3 cell line [68,158]
Invasion and metastasis Apigenin ↓uPA, ↓MMP-2, ↓MMP-9
↑E-cadherin
↓vimentin		 DU-145 cell line
TRAMP mice		 [117,139]
EGCG, gallic acid, genistein ↓MMPs PC-3, DU-145 [90,133,163,164,165]
Angiogenesis apigenin, genistein, quercetin, EGCG ↓VEGF PC-3
TRAMP mice
Men of ages 18 to 75 years with PCa		 [117,164,171,172]
Oncogenes and the coding proteins Curcumin, EGCG ↓c-Jun (Ser73) LNCaP, DU-145 cell lines [90,177]
Tumor suppressor genes and the coding proteins Apigenin ↑p53
↑p27/Kip1
↑p21/CIP1		 22Rv1, LNCaP, PC-3 cell lines
TRAMP mice 		[125,150]
Curcumin ↑p53 PC-3 cell line [119]
EGCG ↑p53, ↑p21/CIP1 LNCaP cell line [154]
DNA methylation and histone modification Curcumin ↓p300-HAT
↓H3 acetylation		 PC-3M cell line [184]
Genistein ↓DNA methylation of RARβ
↓BTG3 gene methylation		 LNCaP, PC-3 cell lines [185,186]
miRNA EGCG ↓oncogenic miR-21
↑tumor suppressor miR-330		 LNCaP, 22Rv1 cell lines [113]
Genistein ↓oncogenic miR-151
↑tumor suppressor miR-574-3p		 LNCaP, PC-3, DU-145 PCa cell lines
RWPE-1 non-malignant epithelial prostate cell line		 [73]
Resveratrol ↓oncogenic miR-21 Highly invasive PC-3M-MM2, DU-145, LNCaP cell lines [79]

Legend: ROS, reactive oxygen species; SOD, superoxide dismutase; CAT, catalase; GPx, glutathione peroxidase; GSR, glutathione reductase; EGCG, epigallocatechin gallate; AR, androgen receptor; HSP90, heat shock protein 90; IGF-1, insulin-like growth factor 1; EGFR, epidermal growth factor receptor; HER2, receptor tyrosine kinase ErbB2/v-ErbB2 avian erithroblastic leukemia viral homolog 2; CXCL-1, -2, chemokine with CXC motif ligand -1, -2; c-Met/HGF, hepatocyte growth factor; PI3K, phosphatidylinositol 3-kinase; Akt, Ak tymoma protein/PKB, protein kinase B; ERK 1/2, extracelluar signal-regulated kinases -1, -2; FoxO, forkhead box O protein; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; mTOR, mammalian target of rapamacyn; GSK-3β, glycogen synthase kinase; PDK1, phosphoinositide-dependent kinase-1; IκBα, inhibitor of NF-κB; SOS, son of sevenless; GRB2, growth factor receptor-bound protein 2; PKC, protein kinase C, JNK, c-Jun N-terminal kinase; MAPK, mitogen activated protein kinase; MRP1, multidrug resistance-associated protein 2; PTEN, phosphatase and tensin homolog; cdc25, cell cycle division protein 25; CHK1, checkpoint kinase 1; caspase-3, cysteine-aspartic acid protease 3; ΔΨm, mitochondrial membrane potential; Bcl-2, B-cell lymphoma type 2 protein; Bcl-XL, Bcl-2 extralarge protein; Bax, Bcl-2-associated X protein; TRAIL, TNF-related apoptosis-inducing ligand; DG5, death receptor; PARP, poly(ADP-ribose) polymerase; CHOP, CCAAT-enhancer-binding protein homologous protein; GADD153, growth arrest and DNA damage inducible Protein 153 protein; ATF, activating transcription factor; GRP78, glucose regulated protein of 78 kDa; uPA, urokinase-type plasminogen activator; MMP-2, matrix metalloproteinase 2; VEGF, vascular endothelial factor; c-Jun, avian sarcoma virus 17 homolog; p27/Kip1, kinesin-like protein; p21/CIP1, cyclin-dependent kinase inhibitor 1A/CDK-interacting protein 1; RARβ, retinoic acid receptor beta; BTG3, B-cell translocation gene; miR, microRNA.