Involvement of Protein Kinase C Activation and Cell Survival/ Cell Cycle Genes in Green Tea Polyphenol (−)-Epigallocatechin 3-Gallate Neuroprotective Action

Levites, Yona; Amit, Tamar; Youdim, Moussa B. H.; Mandel, Silvia

doi:10.1074/jbc.m202832200

Cited by 393 publications

(348 citation statements)

References 57 publications

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“…Interestingly, we observed a decrease in the levels of MDM2 protein in response to EGCG treatment. We speculate that this decrease may be directly mediated by EGCG at the transcriptional level (Levites et al, 2002) or as a result of EGCG-mediated increase in p14 ARF levels (Jackson et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

“…Accumulating evidence shows that dietary factors can activate apoptosis (Ahmad et al, 1997). Recent studies indicate that green tea and its polyphenolic constituents exert inhibitory effect on the activity of several enzymatic and metabolic pathways of relevance to the development and progression of cancer (Levites et al, 2002;Pianetti et al, 2002). EGCG, by virtue of its ability to selectively induce apoptosis in cancer cells and not in normal cells, is potentially an important cancer chemopreventive agent.…”

Section: Discussionmentioning

confidence: 99%

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Role of p53 and NF-κB in epigallocatechin-3-gallate-induced apoptosis of LNCaP cells

et al. 2003

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We have recently shown that oral consumption of green tea polyphenols inhibits prostate carcinogenesis in transgenic mouse model of prostate cancer and suggested that induction of apoptosis in prostate cancer cells is responsible for these effects. Much of the chemopreventive effects of green tea are attributed to its major polyphenolic constituent (À) epigallocatechin-3-gallate (EGCG). In the present study, we report that EGCGinduced apoptosis in human prostate carcinoma LNCaP cells is mediated via modulation of two related pathways: (a) stabilization of p53 by phosphorylation on critical serine residues and p14 ARF -mediated downregulation of murine double minute 2(MDM2) protein, and (b) negative regulation of NF-jB activity, thereby decreasing the expression of the proapoptotic protein Bcl-2. EGCGinduced stabilization of p53 caused an upregulation in its transcriptional activity, thereby resulting in activation of its downstream targets p21/WAF1 and Bax. Thus, EGCG had a concurrent effect on two important transcription factors p53 and NF-jB, causing a change in the ratio of Bax/Bcl-2 in a manner that favors apoptosis. This altered expression of Bcl-2 family members triggered the activation of initiator capsases 9 and 8 followed by activation of effector caspase 3. Activation of the caspases was followed by poly (ADP-ribose) polymerase cleavage and induction of apoptosis. Taken together, the data indicate that EGCG induces apoptosis in human prostate carcinoma cells by shifting the balance between pro-and antiapoptotic proteins in favor of apoptosis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Role of p53 and NF-κB in epigallocatechin-3-gallate-induced apoptosis of LNCaP cells

et al. 2003

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“…In addition to these effects, recent studies have also indicated that they are capable of modulating signal transduction pathways and of regulating gene expression, and that these effects may also contribute to the neuroprotective effects of these compounds (29,167) . For example, in vitro and in vivo studies suggest an ability of green tea catechins to regulate apoptotic pathways (168,169) as well as cell survival-related kinase signalling pathways, such as mitogen-activated protein kinase (170) , PKC (171) and phosphoinositide 3-kinase-Akt (172) . A great deal of research has been devoted to the ability of green tea catechins, especially EGC-3-gallate, to activate the PKC pathway (171,173,174) .…”

Section: Green Teamentioning

confidence: 99%

“…For example, in vitro and in vivo studies suggest an ability of green tea catechins to regulate apoptotic pathways (168,169) as well as cell survival-related kinase signalling pathways, such as mitogen-activated protein kinase (170) , PKC (171) and phosphoinositide 3-kinase-Akt (172) . A great deal of research has been devoted to the ability of green tea catechins, especially EGC-3-gallate, to activate the PKC pathway (171,173,174) . Notably, a 2-week pretreatment with a green tea catechin (EGC-3-gallate) was shown to be protective against Ab-induced neurotoxicity by attenuating the depletion of PKC isoforms in the hippocampus and decreasing amyloid precursor protein (173) .…”

Section: Green Teamentioning

confidence: 99%

Flavonoids as modulators of memory and learning: molecular interactions resulting in behavioural effects

Rendeiro

Guerreiro

et al. 2012

Proc. Nutr. Soc.

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There is considerable interest in the potential of a group of dietary-derived phytochemicals known as flavonoids in modulating neuronal function and thereby influencing memory, learning and cognitive function. The present review begins by detailing the molecular events that underlie the acquisition and consolidation of new memories in the brain in order to provide a critical background to understanding the impact of flavonoid-rich diets or pure flavonoids on memory. Data suggests that despite limited brain bioavailability, dietary supplementation with flavonoid-rich foods, such as blueberry, green tea and Ginkgo biloba lead to significant reversals of age-related deficits on spatial memory and learning. Furthermore, animal and cellular studies suggest that the mechanisms underpinning their ability to induce improvements in memory are linked to the potential of absorbed flavonoids and their metabolites to interact with and modulate critical signalling pathways, transcription factors and gene and/or protein expression which control memory and learning processes in the hippocampus; the brain structure where spatial learning occurs. Overall, current evidence suggests that human translation of these animal investigations are warranted, as are further studies, to better understand the precise cause-and-effect relationship between flavonoid intake and cognitive outputs. Flavonoids: Memory: Learning: HippocampusDiet is an important lifestyle factor, which in recent times has been investigated for its influence on cognitive function and the incidence and onset of neurodegenerative disorders (1,2) . It has long been known that a diet high in saturated fats negatively impacts on cognitive processing and increases the risk of neurological dysfunction in both animals and human subjects (3,4) , while energy restriction (reduction in approximately 30 % energy intake) protects the brain from injury (5,6) . Recently, significant evidence has emerged to indicate that phytochemical-rich foods, and in particular those rich in flavonoids, may reverse agerelated deficits in cognitive function in both animals and human subjects (7)(8)(9) . For example, the PAQUID prospective study examined cognitive performance in 1640 subjects (aged at least 65 years and cognitively normal at baseline) on four occasions over a 10-year-period and found that flavonoid-intake was associated with a significantly better cognitive performance over time (7) (P = 0 . 046). Furthermore, a cross-sectional study examining the relationship between the intake of three common flavonoid-containing foods (chocolate, wine and tea) and cognitive performance in elderly individuals revealed that there was a dose-dependent, positive relationship between the intake of these foods and performance on multiple cognitive outcomes (Kendrick Object Learning Test, Digit Symbol Test, Block Design, Mini-Mental State Examination and Controlled Oral Word Association Test) (10) . More recently, the consumption of dietary flavonoids, especially

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“…For example, the neuroprotective action of one of the green tea flavonoids, epigallocatechin gallate, has been shown in both oxidative stress-(4) and A␤-induced (5) neuronal death models. Protective effects in both systems were linked to a modulation in signaling through protein kinase C and/or modulation of cell survival/cell cycle genes (4,6). Much evidence also exists to support the potential beneficial and neuromodulatory effects of flavonoid-rich ginkgo biloba extracts, such as EGb 761, in the central nervous system (7)(8)(9).…”

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confidence: 99%

Modulation of Pro-survival Akt/Protein Kinase B and ERK1/2 Signaling Cascades by Quercetin and Its in Vivo Metabolites Underlie Their Action on Neuronal Viability

Spencer

Rice‐Evans

Williams

2003

Journal of Biological Chemistry

313

224

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Much recent interest has focused on the potential of flavonoids to interact with intracellular signaling pathways such as with the mitogen-activated protein kinase cascade. We have investigated whether the observed strong neurotoxic potential of quercetin in primary cortical neurons may occur via specific and sensitive interactions within neuronal mitogen-activated protein kinase and Akt/protein kinase B (PKB) signaling cascades, both implicated in neuronal apoptosis. Quercetin induced potent inhibition of both Akt/PKB and ERK phosphorylation, resulting in reduced phosphorylation of BAD and a strong activation of caspase-3. High quercetin concentrations (30 M) led to sustained loss of Akt phosphorylation and subsequent Akt cleavage by caspase-3, whereas at lower concentrations (<10 M) the inhibition of Akt phosphorylation was transient and eventually returned to basal levels. Lower levels of quercetin also induced strong activation of the pro-survival transcription factor cAMP-responsive element-binding protein, although this did not prevent neuronal damage. O-Methylated quercetin metabolites inhibited Akt/PKB to lesser extent and did not induce such strong activation of caspase-3, which was reflected in the lower amount of damage they inflicted on neurons. In contrast, neither quercetin nor its O-methylated metabolites had any measurable effect on c-Jun N-terminal kinase phosphorylation. The glucuronide of quercetin was not toxic and did not evoke any alterations in neuronal signaling, probably reflecting its inability to enter neurons. Together these data suggest that quercetin and to a lesser extent its O-methylated metabolites may induce neuronal death via a mechanism involving an inhibition of neuronal survival signaling through the inhibition of both Akt/PKB and ERK rather than by an activation of the c-Jun N-terminal kinase-mediated death pathway.

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Involvement of Protein Kinase C Activation and Cell Survival/ Cell Cycle Genes in Green Tea Polyphenol (−)-Epigallocatechin 3-Gallate Neuroprotective Action

Cited by 393 publications

References 57 publications

Role of p53 and NF-κB in epigallocatechin-3-gallate-induced apoptosis of LNCaP cells

Role of p53 and NF-κB in epigallocatechin-3-gallate-induced apoptosis of LNCaP cells

Flavonoids as modulators of memory and learning: molecular interactions resulting in behavioural effects

Modulation of Pro-survival Akt/Protein Kinase B and ERK1/2 Signaling Cascades by Quercetin and Its in Vivo Metabolites Underlie Their Action on Neuronal Viability

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