Concomitant inhibition of HSP90, its mitochondrial localized homologue TRAP1 and HSP27 by green tea in pancreatic cancer HPAF‐II cells

Zhang, Zuo‐Feng; Pang, Eric; Loo, Rachel R. Ogorzalek; Rao, Jianyu; Go, Vay-Liang W.; Loo, Joseph A.; Lu, Qing-Yi

doi:10.1002/pmic.201100242

Cited by 28 publications

(32 citation statements)

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“…Green tea and EGCG induce growth inhibition and apoptosis in various pancreatic cancer cell lines (Zhang et al, 2011; Takada et al, 2002). In particular, EGCG inhibits the growth of MIA PaCa-2 pancreatic adenocarcinoma cells with IC 50 in the range of 25-50 μM and induces apoptosis in several studies (Takada et al , 2002; Qanungo et al , 2005; Li et al , 2009).…”

Section: Introductionmentioning

confidence: 99%

“…Recently, we have reported that a green tea extract (GTE) significantly down-regulated LDHA in HPAF-II pancreatic cancer cells using global proteomics profiling (Zhang et al , 2011) Additionally, GTE concomitantly inhibited molecular chaperones heat shock proteins (Hsp) Hsp90, its mitochondrial localized homologue Trap1 (tumor necrosis factor receptor-associated protein 1), Hsp27, phosphor-Akt and induced apoptosis and growth suppression of the cells. These proteomic modifications are likely linked to the alterations in cellular metabolism.…”

Section: Introductionmentioning

confidence: 99%

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Metabolic consequences of LDHA inhibition by epigallocatechin gallate and oxamate in MIA PaCa-2 pancreatic cancer cells

Zhang

Yee

et al. 2014

Metabolomics

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Lactate dehydrogenase A (LDHA) is the enzyme that converts pyruvate to lactate and oxidizes the reduced form of nicotinamide adenine dinucleotide (NADH) to NAD+. Several human cancers including the pancreas display elevated expression of LDHA. Because of its essential role in cancer metabolism, LDHA has been considered to be a potential target for cancer therapy. Recently, we have shown that a green tea extract significantly down-regulated LDHA in HPAF-II pancreatic cancer cells using global proteomics profiling. The present study is to investigate how EGCG, a major biological active constituent of green tea, targets the metabolism of human pancreatic adenocarcinoma MIA PaCa-2 cells. We compared the effect of EGCG to that of oxamate, an inhibitor of LDHA, on the multiple metabolic pathways as measured by extracellular lactate production, glucose consumption, as well as intracellular aspartate and glutamate production, fatty acid synthesis, acetyl-CoA, RNA ribose and deoxyribose. Specific metabolic pathways were studied using [1, 2-13C2]-d-glucose as the single precursor metabolic tracer. Isotope incorporations in metabolites were analyzed using gas chromatography/mass spectrometry (GC/MS) and stable isotope-based dynamic metabolic profiling (SiDMAP). We found that the EGCG treatment of MIA PaCa-2 cells significantly reduced lactate production, anaerobic glycolysis, glucose consumption and glycolytic rate that are comparable to the inhibition of LDHA by oxamate treatment. Significant changes in intracellular glucose carbon re-distribution among major glucose-utilizing macromolecule biosynthesis pathways in response to EGCG and oxamate treatment were observed. The inhibition of LDHA by EGCG or oxamate impacts on various pathways of the cellular metabolic network and significantly modifies the cancer metabolic phenotype. These results suggest that phytochemical EGCG and LDHA inhibitor oxamate confer their anti-cancer activities by disrupting the balance of flux throughout the cellular metabolic network.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Metabolic consequences of LDHA inhibition by epigallocatechin gallate and oxamate in MIA PaCa-2 pancreatic cancer cells

Zhang

Yee

et al. 2014

Metabolomics

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“…Moreover, inhibiting both TRAP1 and related HSPs may be an effective strategy to manipulate cancers, although this has only been demonstrated at the cellular level (Zhang et al 2011). Zhang's group administered green tea extract (GTE) to human pancreatic ductal adenocarcinoma HPAF-II cells and performed two-dimensional gel electrophoresis of the cell lysates.…”

Section: Apoptosismentioning

confidence: 99%

“…Although TRAP1 and HSP90 seem to work independently and be functionally redundant in mitochondria, use of current inhibitors containing gamitrinibs has not been successful in distinguishing the two. Targeting multiple proteins that are overexpressed in various cancer cells, such as HSPs and TRAP1, may be another strategy for cancer therapy; while not specific, it can be effective, as has been seen with GTEs (Zhang et al 2011). Lee et al tried to develop mitochondrial TRAP1 inhibitors and replaced the isopropyl amine of the Hsp90 inhibitor PU-H71 with the mitochondria-targeting moiety triphenylphosphonium to produce SMTIN-P01, which showed TRAP1-specific activity and had improved cytotoxicity to cancer cells .…”

Section: Inhibitors Targeting Trap1mentioning

confidence: 99%

Past, present, and emerging roles of mitochondrial heat shock protein TRAP1 in the metabolism and regulation of cancer stem cells

2016

Cell Stress and Chaperones

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Tumor necrosis factor receptor-associated protein 1 (TRAP1), a member of the HSP90 family, controls a variety of physiological functions, including cell proliferation, differentiation, and survival. Most studies have been devoted to understanding the anti-apoptotic roles of TRAP1 in cancer and targeting it for tumor control in clinical settings. Additionally, we have identified a new role for TRAP1 in regulation of liver regeneration after partial hepatectomy in TRAP1 transgenic mice and cellular proliferation in TRAP1-overexpressing cells, via mitochondrial alterations. Moreover, recent works have indicated a role for TRAP1 in the regulation of cancer stem cells (CSCs) as well as a metabolic switch between mitochondrial respiration and aerobic glycolysis called as BWarburg effect.^This review discusses the implications of TRAP1 action for both metabolism and the regulation of CSCs.

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“…Diverse beneficial effects to prevent cancer, high cholesterol, allergy and diabetes are also reported. [1][2][3][4] Epigallocatechin gallate (EGCG) is a characteristic constituent of green tea and is known to exert diverse effect of green tea.…”

Section: Introductionmentioning

confidence: 99%

Effect of Extraction Conditions of Green Tea on Antioxidant Activity and EGCG Content: Optimization using Response Surface Methodology

et al. 2016

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− Green tea, the leaves of Camellia sinsneis (Theaceae), is generally acknowledged as the most consumed beverage with multiple pharmacological functions including antioxidant activity. This study was performed to analyze the effect of extraction conditions of green tea on its antioxidant effects using DPPH assay. Three extraction factors such as extraction solvent (EtOH, 0 -100%), extraction time (3 -15 min) and extraction temperature (10 -70 o C) were analyzed and optimized extraction condition for antioxidant activity of green tea extract (GTE) was determined using response surface methodology with three-level-three-factor Box-Behnken design (BBD). Regression analysis showed a good fit of data and the optimal conditions of extraction were found to be 57.7% EtOH, 15 min and 70 o C. Under this condition, antioxidant activity of experimental data was 88.4% which was almost fit to the ideal value of 88.6%. As epigallocatechin gallate (EGCG) is known for the major ingredient for antioxidant activity of green tea, we investigated the effect of EGCG on antioxidant activity of GTE. EGCG showed antioxidant activity with the IC 50 value of 4.2 µg/ml and a positive correlation was observed between EGCG content and the antioxidant activity of GTE with R² = 0.7134. Interestingly, however, GTE with 50 -70% antioxidant activity contain less than 1.0 µg/ml of EGCG, which is much lower than IC 50 value of EGCG. Therefore, we suppose that EGCG together with other constituents contribute to antioxidant activity of GTE. Taken together, these results suggest that green tea is more beneficial than EGCG alone for antioxidant ability and optimal extraction condition of green tea will be useful for the development of food and pharmaceutical applications

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Concomitant inhibition of HSP90, its mitochondrial localized homologue TRAP1 and HSP27 by green tea in pancreatic cancer HPAF‐II cells

Cited by 28 publications

References 50 publications

Metabolic consequences of LDHA inhibition by epigallocatechin gallate and oxamate in MIA PaCa-2 pancreatic cancer cells

Metabolic consequences of LDHA inhibition by epigallocatechin gallate and oxamate in MIA PaCa-2 pancreatic cancer cells

Past, present, and emerging roles of mitochondrial heat shock protein TRAP1 in the metabolism and regulation of cancer stem cells

Effect of Extraction Conditions of Green Tea on Antioxidant Activity and EGCG Content: Optimization using Response Surface Methodology

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