Resveratrol sensitizes androgen independent prostate cancer cells to death‐receptor mediated apoptosis through multiple mechanisms

Gill, Catherine; Walsh, Sinead; Morrissey, Colm; Fitzpatrick, John M.; Watson, R. William G.

doi:10.1002/pros.20653

Cited by 76 publications

(63 citation statements)

References 54 publications

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“…These may have important potential implications, as they directly relate to the unsettled issue of bioavailability of resveratrol as well as provide support to recent reports showing that resveratrol sensitizes cancer cells to other chemotherapeutic agents, which act by binding to cell surface death receptors, for example, TRAIL [31]. Data showing that resveratrol increases its own uptake, as illustrated by our experiments using normal prostate cells, also raise the tantalizing possibility that resveratrol might perturb membrane structure and function in ways that facilitate the targeting of death receptors and, hence, improve responsiveness to chemotherapeutic agents without compromising the likelihood for developing chemoresistance [31][32][33]. It is noteworthy to point out that the present studies also showed considerable binding of [ 3 H]resveratrol to cell extracts of PrSCs and PrECs, even when cells are immediately harvested after labeling with resveratrol, and that there was 1.6-fold labeling in PrECs compared with PrSCs ( Figure 1).…”

Section: Discussionsupporting

confidence: 56%

Uptake of resveratrol and role of resveratrol-targeting protein, quinone reductase 2, in normally cultured human prostate cells

Hsieh

2009

Asian J Androl

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AbtractResveratrol is a dietary polyphenol espoused to have chemopreventive activity against a variety of human cancer types. We first reported that resveratrol significantly decreases the proliferation of both androgen-dependent and hormone-refractory prostate cancer cells. However, the effects of resveratrol in normal prostate epithelial and stromal cells, particularly with regard to its uptake, subcellular distribution and intracellular targets, have not been investigated. To advance the knowledge on accessibility and cellular disposition of resveratrol in prostate cells, [ 3 H] resveratrol, fractionation of cell extracts into subcellular compartments, Western blot analysis, resveratrol affinity column chromatography and flow cytometry were used to study the uptake and intracellular distribution of resveratrol in normally cultured prostate stromal (PrSCs) and epithelial cells (PrECs). Pretreatment of both PrSCs and PrECs for 2 days with resveratrol modulated its uptake and selectively increased its distribution to the membrane and organelle compartments. Resveratrol affinity column chromatography studies showed differential expression of a previously identified resveratrol-targeting protein, quinone reductase 2 (QR2), in PrSCs and PrECs. Flow cytometric analysis comparing resveratrol-treated and untreated PrSCs showed a large decrease in G 1 -phase and a concomitant increase in S and G 2 /M-phases of the cell cycle. These results suggest that resveratrol suppresses PrSC proliferation by affecting cell cycle phase distribution, which may involve the participation by QR2.

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Section: Discussionsupporting

confidence: 56%

Uptake of resveratrol and role of resveratrol-targeting protein, quinone reductase 2, in normally cultured human prostate cells

Hsieh

2009

Asian J Androl

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“…24 To further investigate the biochemical mechanisms involved we next looked at the activation of the caspase cascade and demonstrated that TRAIL induces apoptosis by the activation of Caspases 8, 9 and 7 as previously described. 16 Pre-exposure of the cells to hypoxia significantly prevented the activation of these caspases, which was associated with their resistance to apoptosis. Nagaraj et al has recently demonstrated a similar effect of hypoxia on TRAIL-induced Caspases 3, 8 and 9 activation in oral squamous cell carcinoma cells.…”

Section: Discussionmentioning

confidence: 95%

“…Protein concentration of each sample was determined by the Bradford method and activity was expressed as change in fluorescence/min/ mg of protein. 16 …”

Section: Caspase Activity Assaysmentioning

confidence: 99%

“…sicIAP2 (2.25 nM), which specifically targets cIAP2 as previously described 16 and purchased from Dharmacon (Chicago, IL) as part of the SMART pool series and the corresponding non-targeting siRNA control (2.25 nM), as well as Lipofectamine control were made up in prewarmed OptiMEM medium. Each was then mixed by inversion and incubated at room temperature for 5 min.…”

Section: Sirna Transfection To Knockdown Ciap2mentioning

confidence: 99%

“…After 20 min, the remaining Lipofectamine-OptiMEM mix was topped up with an equal volume of OptiMEM. 16 …”

Section: Sirna Transfection To Knockdown Ciap2mentioning

confidence: 99%

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Hypoxia increases normal prostate epithelial cell resistance to receptor‐mediated apoptosis via AKT activation

Walsh

Gill

O’Neill

et al. 2009

Intl Journal of Cancer

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The aging prostate is associated with changes in its vascular structure, which could lead to changes in oxygen levels. Hypoxia is an important environmental change that leads to the progression of many cancers mediated through a number of cellular changes, which included resistance to apoptosis. The role of hypoxia in initiating tumour development has not been previously investigated. We demonstrate that normal prostate epithelial cells develop a resistance to receptor-mediated apoptosis following 24 hr of 1% hypoxia. This effect is associated with the altered expression of a number of pro-and anti-apoptotic proteins, which leads to inhibition of Cytochrome c release and downstream caspase activation. This is mediated via decreased Bax translocation and upstream Caspase 8 activity. Despite increased expression of cIAP-2, small interfering RNA (siRNA) knockdown does not restore susceptibility to TRAIL-induced apoptosis. Gene expression analysis indicated potential changes in AKT activation, which was confirmed by increased phosphorylation of AKT. Inhibition of this phosphorylation reversed the resistance to TRAIL-induced apoptosis. AKT activation is emerging as a key survival signal in prostate cancer. This study demonstrates that short exposure to low oxygen can increase resistance to immune surveillance mechanisms and might confer a survival advantage onto normal prostate epithelial cells so that they can survive subsequent genomic instability and other carcinogenetic insults leading to the early development of prostate cancer. ' 2008 Wiley-Liss, Inc.Key words: hypoxia; prostate; apoptosis; inhibitor of apoptosis; AKT One of the most significant risk factors for the development of prostate cancer is age. Ageing has been associated with progressive changes of physiological functions with time. One example is the increase in tissue hypoxia of organs such as the kidneys 1 and brain. 2 Additionally, with advancing age, the incidence of ischaemic disease increases, for example, those of acute myocardial infarction and stroke. 3 The prostate is also associated with the development of age-related disease. For instance, benign prostatic hyperplasia (BPH) occurs in 20% of men aged 40 years and in 70% of men aged 60 years. Autopsy studies have shown that men aged between 20 and 29 years show evidence of high-grade prostatic intraepithelial neoplasia (PIN) (7.14%) and foci of prostate cancer (3.14%), which increases in men aged 50-59 years, who have increased incidences of PIN (23.8%) and prostate cancer (38.06%). 4 Although hypoxia is most frequently associated with malignancy, with >70% of prostate cancer displaying upregulated HIF1a, 5 the normal aging prostate is also thought to be associated with an hypoxic environment, with the ageing cardiovascular system leading to an age-associated decline in prostatic blood flow. 6 Additionally, men with clinical cardiovascular disease/atherosclerosis or hypertension are at an increased risk for BPH development. 7 Damage to the vascular region of the prostatic transitional zone...

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Resveratrol: The Biochemistry Behind Its Anticancer Effects

Kundu

Surh

2009

Plant Phenolics and Human Health

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Resveratrol sensitizes androgen independent prostate cancer cells to death‐receptor mediated apoptosis through multiple mechanisms

Cited by 76 publications

References 54 publications

Uptake of resveratrol and role of resveratrol-targeting protein, quinone reductase 2, in normally cultured human prostate cells

Uptake of resveratrol and role of resveratrol-targeting protein, quinone reductase 2, in normally cultured human prostate cells

Hypoxia increases normal prostate epithelial cell resistance to receptor‐mediated apoptosis via AKT activation

Resveratrol: The Biochemistry Behind Its Anticancer Effects

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