Detrimental effect of Hypoxia-inducible factor-1α-induced autophagy on multiterritory perforator flap survival in rats

Wang, Long; Jin, Zhi-Cheng; Wang, Jieke; Shao, Chen; Li, Dai; Lin, Dong; Wu, Lei; Gao, Weiyang

doi:10.1038/s41598-017-12034-x

Cited by 25 publications

(20 citation statements)

References 51 publications

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“…We also asked whether preventing degradation of HIF-1α independently of V-ATPase would inhibit AR expression. Dimethyloxalylglycine (DMOG) is a cell permeable prolyl-4-hydroxylase inhibitor, which prevents HIF-1α hydroxylation and its subsequent degradation [ 54 , 55 ]. We hypothesized that treatment with DMOG would mimic CCA-induced iron depletion and would thus increase HIF-1α protein levels and decrease AR expression.…”

Section: Resultsmentioning

confidence: 99%

V-ATPase-dependent repression of androgen receptor in prostate cancer cells

Licon-Munoz

Hayek

et al. 2018

Oncotarget

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Prostate Cancer (PCa) is the most commonly diagnosed cancer and the third leading cause of death for men in the United States. Suppression of androgen receptor (AR) expression is a desirable mechanism to manage PCa. Our studies showed that AR expression was reduced in LAPC4 and LNCaP PCa cell lines treated with nanomolar concentrations of the V-ATPase inhibitor concanamycin A (CCA). This treatment decreased PSA mRNA levels, indicative of reduced AR activity. V-ATPase-dependent repression of AR expression was linked to defective endo-lysosomal pH regulation and reduced AR expression at the transcriptional level. CCA treatment increased the protein level and nuclear localization of the alpha subunit of the transcription factor HIF-1 (HIF-1α) in PCa cells via decreased hydroxylation and degradation of HIF-1α. The addition of iron (III) citrate restored HIF-1α hydroxylation and decreased total HIF-1α levels in PCa cells treated with CCA. Moreover, iron treatment partially rescued CCA-mediated AR repression. Dimethyloxalylglycine (DMOG), which prevents HIF-1α degradation independently of V-ATPase, also decreased AR levels, supporting our hypothesis that HIF-1α serves as a downstream mediator in the V-ATPase-AR axis. We propose a new V-ATPase-dependent mechanism to inhibit androgen receptor expression in prostate cancer cells involving defective endosomal trafficking of iron and the inhibition of HIF-1 α-subunit turnover.

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Section: Resultsmentioning

confidence: 99%

V-ATPase-dependent repression of androgen receptor in prostate cancer cells

Licon-Munoz

Hayek

et al. 2018

Oncotarget

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“…On POD 7, six mice in each group were scanned with a laser doppler instrument (Moor Instruments, Axminster, UK) in a warm and quiet environment under anesthesia. The protocol of LDBF measurement was according to previous study 31. Vascular flow and blood supply were visualized with the LDBF strong signal (green, yellow and red in color).…”

Section: Methodsmentioning

confidence: 99%

Metformin Promotes the Survival of Random-Pattern Skin Flaps by Inducing Autophagy via the AMPK-mTOR-TFEB signaling pathway

Wu¹,

Ding²,

Li³

et al. 2019

Int. J. Biol. Sci.

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Random-pattern skin flaps are widely used to close defects in reconstructive and plastic surgeries; however, they are vulnerable to necrosis, particularly in the distal portion of the flap. Here, we examined the effects of metformin on flap survival and the mechanisms underlying these effects. Following metformin treatment, the survival area, blood flow, and number of microvessels present in skin flaps were increased on postoperative day 7, whereas tissue edema was reduced. In addition, metformin promoted angiogenesis, inhibited apoptosis, relieved oxidative stress, and increased autophagy in areas of ischemia; these effects were reversed by autophagy inhibitors 3-methyladenine (3MA) or chloroquine (CQ). Either 3MA or CQ reversed the metformin-induced increase in flap viability. Moreover, metformin also activated the AMPK-mTOR-TFEB signaling pathway in ischemic areas. Inhibitions of AMPK via Compound C (CC) or AMPK shRNA adeno-associated virus (AAV) vector resulted in the downregulation of the AMPK-mTOR-TFEB signaling pathway and autophagy level in metformin-treated flaps. Taken together, our findings suggest that metformin improves the survival of random-pattern skin flaps by enhancing angiogenesis and suppressing apoptosis and oxidative stress. These effects result from increased autophagy mediated by activation of the AMPK-mTOR-TFEB signaling pathway.

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“…In addition, pretreatment with ATV had a tendency to increase the pmTOR protein expression in the AMCAO group compared with that in the vehicle PMCAO group ( ### p < 0.001); however, 3MA reduced the phospho-mTOR expression in the 3MAMCAO group compared to that in the AMCAO group ( && p < 0.01) ( Figures 5A,D ). In the vehicle PMCAO group, HIF-1α, induced by hypoxia ( Wang et al, 2017 ) and dependent on both mTORC1 and mTORC2 ( Masoud and Li, 2015 ), was increased compared to those in the SHAM controls and AMCAO group ( ∗∗ p < 0.01). In contrast, pretreatment with 3MA resulted in a significant increase of HIF-1α in the 3MAMCAO group compared to the level in the AMCAO group ( &&& p < 0.001, Figures 5E,F ).…”

Section: Resultsmentioning

confidence: 98%

HMG-CoA Reductase Inhibitors Relieve Endoplasmic Reticulum Stress by Autophagy Inhibition in Rats With Permanent Brain Ischemia

Zhang

Yang

et al. 2018

Front. Neurosci.

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Exploring and expanding the indications of common clinical drugs, such as statins, is important to improve the prognosis of patients with permanent cerebral infarction. It has been suggested that reversing the defects in cellular autophagy and ER stress with statin therapy may be a potential treatment option for reducing ischemic damage. Male Sprague-Dawley rats underwent permanent middle cerebral artery occlusion (PMCAO) by electrocoagulation surgery. Atorvastatin (ATV, 10 mg/kg/day) or vehicle was administered intraperitoneally. Rats were divided into the vehicle-treated (SHAM), ATV pretreatment for MCAO (AMCAO), and 3-methyladenine (3MA) combined with ATV pretreatment (3MAMCAO) groups. Magnetic resonance imaging, as well as immunohistochemical and Western blot assessments, were performed 24 h after MCAO. Each ATV-treated group demonstrated significant reductions in infarct volume compared with that in the vehicle-treated group at 24 h after MCAO, which was associated with autophagy reduction and ER stress attenuation in neurons and neovascularization. Next, Western blotting was used to detect the levels of the autophagy-related proteins LC3B and P62 and of ER stress pathway proteins. However, 3MA significantly partially inhibited the ER stress pathway via limiting the autophagic flux in the AMCAO group. In conclusion, our results imply that the neuroprotective function of ATV depends on autophagic activity to diminish ER stress-related cell apoptosis in rats with PMCAO and suggest that compounds that inhibit autophagic activity might reduce the neuroprotective effect of ATV after brain ischemia.

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Detrimental effect of Hypoxia-inducible factor-1α-induced autophagy on multiterritory perforator flap survival in rats

Cited by 25 publications

References 51 publications

V-ATPase-dependent repression of androgen receptor in prostate cancer cells

V-ATPase-dependent repression of androgen receptor in prostate cancer cells

Metformin Promotes the Survival of Random-Pattern Skin Flaps by Inducing Autophagy via the AMPK-mTOR-TFEB signaling pathway

HMG-CoA Reductase Inhibitors Relieve Endoplasmic Reticulum Stress by Autophagy Inhibition in Rats With Permanent Brain Ischemia

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