Resveratrol inhibits the growth of tumor cells under chronic stress via the ADRB‑2‑HIF‑1α axis

Ma, Jiguang; Xue, Mengwen; Zhang, Simei; Liu, Cheng; Qian, Weikun; Duan, Wanxing; Shen, Xin

doi:10.3892/or.2018.6894

Cited by 10 publications

(9 citation statements)

References 29 publications

(31 reference statements)

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“…Rather, we demonstrate that preventing HIF-1α drop restores the correct desensitization cascade of BAR2, indicating a link between HIF-1 and BAR2 upregulation. In this respect, the growth of cancer cells under chronic stress appears to be regulated by the HIF-1/BAR2 axis as demonstrated by the finding that resveratrol inhibits the proliferation of chronically stressed cancer cells by preventing the upregulation of both HIF-1α and BAR2 [ 44 ]. Another possibility is that DMOG acts directly on BAR2 internalization without the intervention of HIF-1.…”

Section: Discussionmentioning

confidence: 99%

Novel Insights into Beta 2 Adrenergic Receptor Function in the rd10 Model of Retinitis Pigmentosa

Cammalleri

Monte

Amato

et al. 2020

Cells

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Background: In retinitis pigmentosa (RP), inherited rod death is followed by cone loss and blindness. Why cones die is still a matter of consideration. Here, we investigate the pathogenic role of the sympathetic transmission in the rd10 mouse model of RP. Methods: Retinal levels of beta adrenergic receptor (BAR) 2 and norepinephrine (NE) were measured. After administration of the BAR1/2 blocker propranolol or the hypoxia-inducible factor (HIF)-1 activator dimethyloxalylglycine (DMOG), retinal levels of HIF-1α, BAR2 or proteins involved in BAR2 desensitization were also measured. In DMOG treated mice, expression and localization of BAR2, inflammatory markers and cone arrestin were determined. Finally, rd10 mice were subjected to electroretinogram (ERG) analysis to assess rod and cone function. Results: In the rd10 retina, BAR2 overexpression and NE accumulation were found, with BAR2 immunoreactivity localized to Müller cells. BAR2 overexpression was likely due to desensitization defects. Upregulated levels of BAR2 were drastically reduced by propranolol that also restored desensitization defects. Due to the low level of HIF-1 consequent to the hyperoxic environment in the rd10 retina, we hypothesized a link between HIF-1 and BAR2. HIF-1α stabilization with DMOG resulted in i. increased HIF-1α accumulation, ii. decreased BAR2 levels, iii. restored desensitization processes, iv. reduced expression of inflammatory markers and v. increased cone survival without improved retinal function. Conclusions: Our results support a pathogenic role of the sympathetic system in RP that might help to understand why rd10 mice show a positive response to BAR blockers.

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Section: Discussionmentioning

confidence: 99%

Novel Insights into Beta 2 Adrenergic Receptor Function in the rd10 Model of Retinitis Pigmentosa

Cammalleri

Monte

Amato

et al. 2020

Cells

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“…The effects of resveratrol upon hypoxia have been mainly related to the transcription and protein accumulation of the hypoxia‐inducible factor 1‐alpha (HIF‐1α), which is induced by a lack of oxygen. The expression of HIF‐1α and cellular viability was diminished in HepG2 human hepatoblastoma cells, SKOV‐3 ovarian carcinoma cells, and BxPC‐3 human pancreatic cancer cells with resveratrol supplementation at 25 and 50 µM (Ma et al, ). Indeed, resveratrol (20 mg/kg of body weight) also decreases mRNA and protein levels of HIF‐1α in the liver of rats induced to an ischemia/reperfusion (Zhang, Li, Yu, & Wu, ).…”

Section: The Relationship Between the Cytotoxic Effect Of Resveratrolmentioning

confidence: 99%

“…Resveratrol cytotoxic effects have been reported in S. cerevisiae (Ramos‐Gomez et al, ), human lung adenocarcinoma ASTC‐a‐1 cells (Zhang, Wang, & Chen, ), human pancreatic Bx‐PC‐3 cancer cells (Ma et al, ), and rat B103 neuroblastoma cells (Rahman, Kim, Kim, Oh, & Huh, ). In addition, mitochondriotropic resveratrol derivatives showed strong cytotoxic effects in mouse colon cancer CT‐26 cells (Sassi, Mattarei, Azzolini, Bernardi, et al, ; Sassi, Mattarei, Azzolini, Szabo, et al, ), suggesting that the cytotoxic mechanism of resveratrol should be universal for several eukaryotic cells.…”

Section: The Relationship Between the Cytotoxic Effect Of Resveratrolmentioning

confidence: 99%

Resveratrol cytotoxicity is energy‐dependent

2019

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Resveratrol is a phytochemical that may promote health. However, it has also been reported to be a toxic compound. The molecular mechanism by which resveratrol acts remains unclear. The inhibition of the oxidative phosphorylation (OXPHOS) pathway appears to be the molecular mechanism of resveratrol. Taking this into account, we propose that the cytotoxic properties of resveratrol depend on the energy (e.g., carbohydrates, lipids, and proteins) availability in the cells. In this regard, in a condition with low energy accessibility, resveratrol could enhance ATP starvation to lethal levels. In contrast, when cells are supplemented with high quantities of energy and resveratrol, the inhibition of OXPHOS might produce a low‐energy environment, mimicking the beneficial effects of caloric restriction. This review suggests that investigating a possible complex relationship between caloric intake and the differential effects of resveratrol on OXPHOS may be justified. Practical applications A low‐calorie diet accompanied by significant levels of resveratrol might modify cellular bioenergetics, which could impact cellular viability and enhance the anti‐cancer properties of resveratrol.

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“…However, the upregulation of HIF-1α that is independent of hypoxia is still unclear. Previous studies showed that the expression of HIF-1α in tumor tissue increased under chronic stress (8)(9)(10)(11), and β2-AR-HIF-1α axis can regulate the stress-induced pancreatic tumor growth and angiogenesis (11). The relationship between psychological stress stimulation and hypoxia-independent HIF-1α pathway activation in tumors needs to be further clarified.…”

Section: Introductionmentioning

confidence: 97%

Psychologic Stress Drives Progression of Malignant Tumors via DRD2/HIF1α Signaling

et al. 2021

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Although it is established that the sustained psychological stress conditions under which tumor patients often reside accelerates malignant progression of tumors, the molecular mechanism behind this association is unclear. In this work, the effect of psychological stress on tumor progression was verified using a stress-stimulated tumor-bearing mouse model (Str-tumor). Both D2 dopamine receptor (DRD2) and hypoxia-inducible factor 1-alpha (HIF-1α) were highly expressed in the nucleus of stress-stimulated tumors. Treatment with trifluoperazine (TFP), a DRD2 inhibitor, elicited better antitumor effects in Str-tumors than the control group. These results indicate that DRD2 may mediate stress-induced malignant tumor progression. DRD2 interacted with von Hippel-Lindau (VHL) in the nucleus, and competitive binding of DRD2 and HIF-1α to VHL resulted in reduced ubiquitination-mediated degradation of HIF-1α, enhancing the epithelial-mesenchymal transition (EMT) of tumor cells. TFP acted as an interface inhibitor between DRD2 and VHL to promote the degradation of HIF-1α. In conclusion, DRD2 may promote the progression of malignant tumors induced by psychological stress via activation of the oxygen-independent HIF-1α pathway, and TFP may serve as a therapeutic strategy for stress management in cancer patients. SignificanceThis work identifies DRD2 regulation of HIF-1α as mechanism underlying the progression of malignant tumors stimulated by psychological stress and suggests that DRD2 inhibition can mitigate these stress conditions in patients.Research.

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Resveratrol inhibits the growth of tumor cells under chronic stress via the ADRB‑2‑HIF‑1α axis

Cited by 10 publications

References 29 publications

Novel Insights into Beta 2 Adrenergic Receptor Function in the rd10 Model of Retinitis Pigmentosa

Novel Insights into Beta 2 Adrenergic Receptor Function in the rd10 Model of Retinitis Pigmentosa

Resveratrol cytotoxicity is energy‐dependent

Psychologic Stress Drives Progression of Malignant Tumors via DRD2/HIF1α Signaling

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