Molecular pathway for (−)-epigallocatechin-3-gallate-induced cell cycle arrest and apoptosis of human prostate carcinoma cells

Gupta, Sanjay; Hussain, Tajamul; Mukhtar, Hasan

doi:10.1016/s0003-9861(02)00668-9

Cited by 264 publications

(179 citation statements)

References 37 publications

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“…p21/WAF1 can inhibit cdk2, 4 and 6 causing cell cycle arrest (Bates and Vousden, 1999). Studies from our laboratory indicate that EGCG-mediated upregulation of p21/WAF1 is critical in inducing both cell cycle arrest and apoptosis (Gupta et al, 2003;Hastak et al, manuscript in preparation). This premise is supported by several independent studies, which show that targeted overexpression of p21/WAF1 increases apoptosis (Fotedar et al, 1999;Shibata et al, 2001).…”

Section: Discussionmentioning

confidence: 88%

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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: 88%

“…This can be because, along with inducing apoptosis, EGCG is also responsible for G1 arrest in the LNCaP cells . Secondly the pathway involving cell cycle deregulation has been studied in one of our recent studies (Gupta et al, 2003). Therefore, difference in cell viability and apoptosis can be explained by cell cycle arrest induced by EGCG.…”

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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“…Ectopic overexpression of p27 KIP1 was reported to initiate apoptosis in several mammalian cells. 47 Accordingly, an increased expression of p27 KIP1 was previously linked to the anti-proliferative and pro-apoptotic properties of the chemopreventive agent epigallocatechin-3-gallate, 48,49 a known antagonist of AHR signaling. 29 The repressive influence of an enhanced p27 KIP1 level on E2F1 expression, observed in our study, may contribute to these beneficial effects.…”

Section: Discussionmentioning

confidence: 99%

Evidence for a novel anti-apoptotic pathway in human keratinocytes involving the aryl hydrocarbon receptor, E2F1, and checkpoint kinase 1

et al. 2013

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Exposure of keratinocytes (KC) to ultraviolet (UV) radiation results in the initiation of apoptosis, a protective mechanism that eliminates cells harboring irreparable DNA damage. Hence, a manipulation of UV-induced apoptosis may significantly influence photocarcinogenesis. We have discovered that the aryl hydrocarbon receptor (AHR), a key regulator of drug metabolism and an UVB-sensitive transcription factor, serves an anti-apoptotic function in UVB-irradiated human KC. Chemical and shRNA-mediated inhibition of AHR signaling sensitized KC to UVB-induced apoptosis by decreasing the expression of E2F1 and its target gene checkpoint kinase 1 (CHK1). The decreased expression of these cell-cycle regulators was due to an enhanced expression of p27 KIP1 and an associated decrease in phosphorylation of both cyclin-dependent kinase 2 and its substrate molecule retinoblastoma protein. The subsequent inhibition of E2F1 autoregulation and downstream CHK1 expression resulted in an enhanced susceptibility of damaged cells to undergo apoptosis. Accordingly, ectopic overexpression of either E2F1 or CHK1 in AHR-knockdown KC attenuated the observed sensitization to UVB-induced apoptosis. Using an AHR-knockout SKH-1 hairless mouse model, we next demonstrated the physiological relevance of the anti-apoptotic function of AHR. In contrast to their AHR-proficient littermates, the constitutive expression of E2F1 and CHK1 was significantly reduced in the skin of AHR-knockout mice. Accordingly, a single exposure of the animals to UVB resulted in an enhanced cleavage of caspase-3 in the skin of AHR-knockout mice. These results identify for the first time the AHR-E2F1-CHK1 axis as a novel anti-apoptotic pathway in KC, which may represent a suitable target for chemoprevention of non-melanoma skin cancer. With an annual incidence of two to three million new cases worldwide, non-melanoma skin cancer (NMSC) is one of the most frequent forms of cancer in humans (World Health Organization; http://www.who.int/uv/faq/skincancer/en/index1 .html). Typically, NMSCs, such as basal cell and squamous cell carcinomas, occur on sun-exposed areas of the skin, indicating that solar ultraviolet (UV) radiation, especially its UVB part (290-320 nm), is the most important etiological factor. 1,2 In fact, it is well established that UVB radiation gives rise to skin cancer without additional initiators or promoters and thus is a complete carcinogen. 1 Because of the thinning of the ozone layer, the increase in recreational sunbathing and the enhanced usage of UV tanning beds, the incidence of NMSC is expected to increase in future years, 1,2 underscoring the urgent need for novel preventives against UV-induced skin malignancies.When skin is exposed to solar radiation, high-energy UVB photons penetrate into the epidermis and initiate the so-called UVB response. 3 The main trigger of this stress response is the absorbance of UVB rays by DNA, which leads to the generation of highly mutagenic DNA photoproducts. 3,4 In addition, UVB exposure results in the formation...

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“…A significant reason for the great interest in EGCG is because of its remarkable effects in many in vitro and in vivo tumor model systems Singh et al, 2002;Chung et al, 2003;Gupta et al, 2003;Hastak et al, 2003). Part of this effect of EGCG appears to be because, at physiologically attainable concentrations, it induces apoptosis in cancer cells without affecting normal cells (Ahmad et al, 1997, 2000; Chen et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

“…Epigallocatechin-3-gallate (EGCG), the major polyphenolic constituent present in green tea, has received much attention over the last few years, as a potential cancerchemopreventive and cancer-chemotherapeutic agent, possibly because of its wide range of effects on a number of cellular processes and efficacy in many tumor model systems (Singh et al, 2002;Chung et al, 2003;Gupta et al, 2003;Hastak et al, 2003). Our previous studies have shown that EGCG, at pharmacologically attainable concentrations, results in inhibition of cell growth, arrest of the cell cycle in G0/G1 phase and induction of apoptosis in some human carcinoma cells (Ahmad et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Essential role of caspases in epigallocatechin-3-gallate-mediated inhibition of nuclear factor kappaB and induction of apoptosis

et al. 2003

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Green tea constituent (À) epigallocatechin-3-gallate (EGCG) has shown remarkable cancer-preventive and some cancer-therapeutic effects. This is partially because of its ability to induce apoptosis in cancer cells without affecting normal cells. Previous studies from our laboratory have shown the involvement of NF-jB pathway in EGCG-mediated cell-cycle deregulation and apoptosis of human epidermoid carcinoma A431 cells. Here we show the essential role of caspases in EGCG-mediated inhibition of NF-jB and its subsequent apoptosis. Treatment of A431 cells with EGCG (10-40 lg/ml) resulted in dosedependent inhibition of NF-jB/p65, induction of DNA breaks, cleavage of poly(ADP-ribose) polymerase (PARP) and morphological changes consistent with apoptosis. EGCG treatment of cells also resulted in significant activation of caspases, as shown by the doseand time-dependent increase in DEVDase activity, and protein expression of caspase-3, -8 and -9. EGCGmediated caspase activation induces proteolytic cleavage of NF-jB/p65 subunit, leading to the loss of transactivation domains, and driving the cells towards apoptosis. EGCG-mediated induction of apoptosis was significantly blocked by the caspase inhibitor N-benzyloxycarbonylVal-Ala-Asp(OMe)-fluoromethylketone (Z-VAD-FMK), and moderately blocked by the specific caspase-3 inhibitor Z-DEVD-FMK. Further, pretreatment of cells with Z-VAD-FMK was found to suppress the cleavage of NF-jB/ p65 subunit, thereby increasing nuclear translocation, DNA binding and transcriptional activity, thus protecting the cells from EGCG-induced apoptosis. Taken together, these studies for the first time demonstrate that EGCGmediated activation of caspases is critical, at least in part, for inhibition of NF-jB and subsequent apoptosis.

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Molecular pathway for (−)-epigallocatechin-3-gallate-induced cell cycle arrest and apoptosis of human prostate carcinoma cells

Cited by 264 publications

References 37 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

Evidence for a novel anti-apoptotic pathway in human keratinocytes involving the aryl hydrocarbon receptor, E2F1, and checkpoint kinase 1

Essential role of caspases in epigallocatechin-3-gallate-mediated inhibition of nuclear factor kappaB and induction of apoptosis

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