Resveratrol Induces Apoptosis in Chemoresistant Cancer Cells via Modulation of AMPK Signaling Pathway

Hwang, Jin‐Taek; Kwak, Dong Wook; Sun, Lin; Kim, Hye Min; Kim, Young Min; Park, Ock Jin

doi:10.1196/annals.1397.047

Cited by 146 publications

(101 citation statements)

References 16 publications

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“…Specifically, we demonstrated that resveratrol turned on AMPK activity both in cell cultures and in vivo in mouse brain after oral dosing and that AMPK inhibition significantly impaired the effect of resveratrol on A␤ accumulation in cell lines and in primary neurons. The observation that resveratrol activates AMPK is in line with previous studies using cell line cultures and animal models (42,(45)(46)(47)(48)(49). For instance, it was shown that resveratrol administered orally through the diet can activate AMPK at the periphery in mouse liver (42).…”

Section: Discussionsupporting

confidence: 85%

AMP-activated Protein Kinase Signaling Activation by Resveratrol Modulates Amyloid-β Peptide Metabolism

Vingtdeux

Giliberto

Zhao

et al. 2010

Journal of Biological Chemistry

583

445

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Alzheimer disease is an age-related neurodegenerative disorder characterized by amyloid-␤ (A␤) peptide deposition into cerebral amyloid plaques. The natural polyphenol resveratrol promotes anti-aging pathways via the activation of several metabolic sensors, including the AMP-activated protein kinase (AMPK). Resveratrol also lowers A␤ levels in cell lines; however, the underlying mechanism responsible for this effect is largely unknown. Moreover, the bioavailability of resveratrol in the brain remains uncertain. Here we show that AMPK signaling controls A␤ metabolism and mediates the anti-amyloidogenic effect of resveratrol in non-neuronal and neuronal cells, including in mouse primary neurons. Resveratrol increased cytosolic calcium levels and promoted AMPK activation by the calcium/ calmodulin-dependent protein kinase kinase-␤. Direct pharmacological and genetic activation of AMPK lowered extracellular A␤ accumulation, whereas AMPK inhibition reduced the effect of resveratrol on A␤ levels. Furthermore, resveratrol inhibited the AMPK target mTOR (mammalian target of rapamycin) to trigger autophagy and lysosomal degradation of A␤. Finally, orally administered resveratrol in mice was detected in the brain where it activated AMPK and reduced cerebral A␤ levels and deposition in the cortex. These data suggest that resveratrol and pharmacological activation of AMPK have therapeutic potential against Alzheimer disease. Alzheimer disease (AD)2 is a progressive neurodegenerative disorder and the first cause of dementia. Amyloid-␤ (A␤) peptides have a central role in the pathogenesis of the disease and represent the core components of the senile plaques, the lesions invariably found in the neocortex and hippocampus of the AD brains (1, 2). In the amyloidogenic pathway, the amyloid-␤ precursor protein (APP) is sequentially cleaved by the aspartic protease ␤-secretase/BACE1 and by the ␥-secretase proteolytic complex to produce various A␤ peptides, including the most abundant isoforms A␤1-40 and A␤1-42 (3, 4).Epidemiological data suggest that moderate consumption of red wine is associated with a lower incidence of dementia and AD (5). The naturally occurring polyphenol resveratrol (trans-3,4Ј,5-trihydroxystilbene), which is found in abundance in red wine, has antioxidant and neuroprotective properties in vitro and could explain, in part, the beneficial effects of wine consumption in AD (6, 7). Importantly, resveratrol controls A␤ levels by facilitating its proteolytic clearance in cultured cell lines (8). However, the exact molecular mechanism by which resveratrol controls A␤ metabolism is currently unknown. Furthermore, evidence is missing to support the notion that orally administered resveratrol is bioavailable and bioactive in the brain.A growing body of literature has demonstrated the beneficial effect of resveratrol on age-related metabolic deterioration and its protective role in metabolic diseases, such as type 2 diabetes and obesity. Resveratrol mimics caloric restriction by extending the lifespan of different smal...

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Section: Discussionsupporting

confidence: 85%

AMP-activated Protein Kinase Signaling Activation by Resveratrol Modulates Amyloid-β Peptide Metabolism

Vingtdeux

Giliberto

Zhao

et al. 2010

Journal of Biological Chemistry

583

445

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“…13,14) In addition, resveratrol, a polyphenolic natural product, 25) induces apoptosis in HT-29 cells via AMPK activation. 26) Our findings demonstrated that AglRhz is able to increase phosphorylation of AMPK and decrease cell viability in HT-29 cells (Figs. 1B, 2A, B).…”

Section: Discussionsupporting

confidence: 52%

Aglycon of Rhizochalin from the Rhizochalina incrustata Induces Apoptosis via Activation of AMP-Activated Protein Kinase in HT-29 Colon Cancer Cells

Khanal

Kang

Yun

et al. 2011

Biological & Pharmaceutical Bulletin

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Rhizocalin is the first two-headed sphingolipid like compound isolated from the sponge Rhizochalina incrustata.1) It has been shown that rhizochalin and its derivatives have antibacterial, selective DNA-damaging, antifungal and cytotoxic activity.1) In addition, accumulating evidence suggests that rhizochalin and its derivatives have potent antitumor activity in human cancer cell lines, including cervical cancer, leukemia, and colon cancer.2,3) However, the underlying mechanisms of its anticarcinogenic activity remain poorly understood.The AMP-activated protein kinase (AMPK), a serine/ theronine kinase present in all eukaryotes, is a sensor of cellular energy status. 4) Since tumor-suppressor genes such as TSC2 and LKB1 function as upstream kinases of AMPK, AMPK is known as an antiproliferative molecule. 5,6) Previous studies have reported that AMPK activators, 5-amino-4-imidazolecarboxamide riboside (AICAR) and metformin, inhibit the cell growth in cultured tumor cells and mouse xenograft models.6-8) AMPK activation also induces apoptosis in cancer cell lines such as neuroblastoma cells, pancreatic cells, glioma cells, and endometrial cancer cells. [9][10][11][12] In addition, AMPK activation by phytochemicals, such as quercetin and 24-hydroxyursolic acid, is involved in apoptosis in colon cancer cell lines 13,14) Therefore, AMPK activation by naturally occurring compounds has attractive potentials for cancer therapy.Here, we have investigated the role of aglycon of rhizochalin (AglRhz), two-headed sphingolipid-like compound isolated from the sponge Rhizochalina incrustata, in the activation of AMPK and induction of apoptosis in HT-29 colon cancer cells. We observed that AglRhz inhibited phosphorylation of p70S6K and its downstream target extracellular signal-regulated kinase (ERK) in a Raptor-dependent manner via AMPK activation. We have also found that AglRhz induced the cleavage of caspase-3 and poly(ADP-ribose) polymerase (PARP), as well as DNA fragmentation, resulting in the induction of apoptosis. In addition, AglRhz inhibited insulin-like growth factor (IGF)-induced cell neoplastic transformation in JB6 Cl41 cells and tumorigenicity in HT-29 cells. Taken together, our findings illustrate that AglRhz has a potent antitumor activity against the HT-29 colon cancer cells and suggests a molecular mechanism that underlies the antitumor activity of AglRhz. MATERIALS AND METHODS Reagents and AntibodiesMcCoy's 5A medium, L-glutamine, gentamicin, and fetal bovine serum (FBS) were purchased from Invitrogen (Carlsbad, CA, U.S.A.). Polyvinyl idene difluoride (PVDF) membrane was obtained from Millipore (Bedford, MA, U.S.A.). 3-[4,5-Dimethylthiazol-2-thiazoyl]-2,5-diphenyltetrazolium bromide (MTT) was from Sigma-Aldrich (St. Louis, MO, U.S.A.). Antibodies against phospho-p70S6K (Thr389), p70S6K, phospho-ERK1/2 (Thr202/Tyr204), ERK1/2, phospho-Raptor (Ser792), phospho-AMPK, cleaved caspase-3, cleaved PARP, caspase-3, and B-cell lymphoma 2 (Bcl-2) were from Cell Signaling Technology Inc. (Beverly, MA, U.S.A.); antibodies...

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“…The effects of metabolic stress such as hypoxia, caloric restriction, or muscle contraction on AMPK signaling in aging are equally equivocal with some studies reporting increased activation (169,379), while others have reported a reduction (349,408). Interestingly, resveratrol (3,5,4Ј-trihydroxystilbene), which extends the life span of organisms through Sir2, a conserved deacetylase, proposed to underlie the beneficial effects of caloric restriction, activates AMPK (121, 220,384,575). While recent studies suggest that the effect of Sir2 on longevity may have more to do with altered insulin and IGF-I signaling than AMPK (292), future studies examining longevity in AMPK null mice will be important.…”

Section: A Aging and Longevitymentioning

confidence: 99%

“…However, the mechanism(s) of action of these compounds has remained largely a mystery, limiting their therapeutic potential. Several recent studies have demonstrated that polyphenols such as resveratrol stimulate AMPK activity in a variety of cell types including liver (575), skeletal muscle (36, 384), neurons (121), and cancer (220). The activation of AMPK by resveratrol may be mediated by AMP as resveratrol inhibits the mitochondrial F1 ATPase (166).…”

Section: Polyphenols and Resveratrolmentioning

confidence: 99%

AMPK in Health and Disease

Steinberg¹,

Kemp²

2009

Physiological Reviews

1,459

1,419

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The function and survival of all organisms is dependent on the dynamic control of energy metabolism, when energy demand is matched to energy supply. The AMP-activated protein kinase (AMPK) αβγ heterotrimer has emerged as an important integrator of signals that control energy balance through the regulation of multiple biochemical pathways in all eukaryotes. In this review, we begin with the discovery of the AMPK family and discuss the recent structural studies that have revealed the molecular basis for AMP binding to the enzyme's γ subunit. AMPK's regulation involves autoinhibitory features and phosphorylation of both the catalytic α subunit and the β-targeting subunit. We review the role of AMPK at the cellular level through examination of its many substrates and discuss how it controls cellular energy balance. We look at how AMPK integrates stress responses such as exercise as well as nutrient and hormonal signals to control food intake, energy expenditure, and substrate utilization at the whole body level. Lastly, we review the possible role of AMPK in multiple common diseases and the role of the new age of drugs targeting AMPK signaling.

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Resveratrol Induces Apoptosis in Chemoresistant Cancer Cells via Modulation of AMPK Signaling Pathway

Cited by 146 publications

References 16 publications

AMP-activated Protein Kinase Signaling Activation by Resveratrol Modulates Amyloid-β Peptide Metabolism

AMP-activated Protein Kinase Signaling Activation by Resveratrol Modulates Amyloid-β Peptide Metabolism

Aglycon of Rhizochalin from the Rhizochalina incrustata Induces Apoptosis via Activation of AMP-Activated Protein Kinase in HT-29 Colon Cancer Cells

AMPK in Health and Disease

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