Protein phosphatase 2A regulation of markers of extracellular matrix remodelling in hepatocellular carcinoma cells: functional consequences for tumour invasion

Ward, Mark P.; Spiers, Paul

doi:10.1111/bph.13759

Cited by 22 publications

(15 citation statements)

References 64 publications

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“…The MMP-2 and MMP-9 protein expression levels were analyzed in the present study and the results demonstrated that the PP2A activator promoted the expression of the MMP-2 and MMP-9 proteins in astrocytes, while the PP2A inhibitor inhibited the expression of MMP-2 and MMP-9 in astrocytes. The results were consistent with that of the cell migration assay and observations that OA can activate MMP-9 ( 31 ).…”

Section: Discussionsupporting

confidence: 91%

Protein phosphatase 2A regulates the p38 signaling pathway to affect the migration of astrocytes

Zhang

Guan

et al. 2018

Mol Med Report

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The aim of the present study was to investigate the effect and mechanism of protein phosphatase 2A (PP2A) on the migration of astrocytes. The primary astrocytes of neonatal mice were isolated and cultured in vitro, and treated with the PP2A activator D-erythro-sphingosine (DES) (activated group) or inhibitor okadaic acid (inhibitory group). The control group was treated with equal amounts of dimethyl sulfoxide. The activity of PP2A in the cells was detected using a commercial kit and the migration of cells was investigated using a Transwell migration assay. The protein expression of p38, phosphorylated (p)-p38, matrix metalloproteinase (MMP)-2 and MMP-9 was detected by western blotting. Cell migration and the protein expression of p38, p-p38, MMP-2 and MMP-9 was also determined following treatment of astrocytes with the p38 signaling pathway inhibitor SB202190 with or without the PP2A activator DES. The results demonstrated that the activity of PP2A in the PP2A inhibitory group was significantly decreased compared with the control group, while that of the PP2A-activated cells was significantly increased compared with the control. The protein levels of MMP-2 and MMP-9 in the PP2A inhibitory group astrocytes were significantly decreased compared with the control group, while PP2A-activated astrocytes exhibited significantly increased levels of these proteins. By contrast, the p-p38 level in PP2A inhibitory group astrocytes was significantly increased compared with the control group, while astrocytes in the activated group exhibited significantly lower levels compared with the control group. Furthermore, the cell migration ability, and MMP-2 and MMP-9 protein levels, of astrocytes that received combined treatment with SB202190 and the PP2A activator DES were significantly increased compared with the levels in astrocytes treated with SB202190 alone. The results of the current study indicate that PP2A may negatively regulate the p38 signaling pathway to promote astrocyte migration.

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Section: Discussionsupporting

confidence: 91%

Protein phosphatase 2A regulates the p38 signaling pathway to affect the migration of astrocytes

Zhang

Guan

et al. 2018

Mol Med Report

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“…VSMC migration was determined using two assays: the transwell migration assay and scratch‐wound migration assay. Transwell migration was performed as described as previously (Ward and Spiers, ). Briefly, this experiment was performed in polycarbonate transwell inserts (5 mm pore, Corning).…”

Section: Methodsmentioning

confidence: 99%

Nicotinic ACh receptor α7 inhibits PDGF‐induced migration of vascular smooth muscle cells by activating mitochondrial deacetylase sirtuin 3

Tong

Zeng

et al. 2018

British J Pharmacology

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Background and Purpose PDGF‐BB is an angiogenic factor involved in cardiovascular diseases. Here, we investigated the possible effects of activation of the nicotinic ACh receptor α7 subtype (α7nAChR) on PDGF‐BB‐induced proliferation and migration in vascular smooth muscle cells (VSMCs). Experimental Approach PNU‐282987, a selective α7nAChR pharmacological agonist, was used to activate α7nAChR. The influences of α7nAChR activation on PDGF‐BB‐induced proliferation and migration, as well as the phosphorylation of focal adhesion kinase (FAK)/Src, a pro‐migration signalling pathway, were determined in VSMCs. A variety of biochemical assays were applied to explore the underlying molecular mechanisms. Key Results PDGF‐BB induced pronounced migration and proliferation of VSMCs. Activation of α7nAChRs by PNU‐282987 blocked PDGF‐BB‐induced migration but not proliferation in wild‐type (WT) VSMCs, whereas this effect was absent in α7nAChR‐knockout VSMCs. Accordingly, PNU‐282987 attenuated PDGF‐BB‐induced phosphorylation of FAKTyr397 and SrcTyr416 in WT VSMCs. Mechanistically, PNU‐282987 suppressed PDGF‐BB‐induced oxidative stress, as demonstrated by the alterations in ROS, H2O2 content, superoxide anion and total antioxidant activity. A sirtuin 3 (SIRT3) inhibitor 3‐(1H‐1,2,3‐triazol‐4‐yl) pyridine or shRNA‐mediated SIRT3 knockdown abolished the inhibitory effect of PNU‐282987. PNU‐282987 did not modulate SIRT3 protein expression but enhanced mitochondrial SIRT3 deacetylase activity. In line with this action, PNU‐282987 enhanced the deacetylation of mitochondrial FoxO3. Lastly, PNU‐282987 corrected the PDGF‐BB‐induced mitochondrial dysfunction by increasing mitochondrial citrate synthase activity, ATP content and nicotinamide adenine dinucleotide pool. Conclusions Pharmacological activation of α7nAChRs inhibits PDGF‐BB‐induced VSMC migration by activating the mitochondrial deacetylase SIRT3, implying an important role for α7nAChRs in mitochondria biology and PDGF‐related diseases. Linked Articles This article is part of a themed section on Mitochondrial Pharmacology: Featured Mechanisms and Approaches for Therapy Translation. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.22/issuetoc

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“…Neoplastic processes can alter the ECM comopsition. [44][45][46][47] Although hematoxylin and eosin (H&E) staining is the standard diagnostic method for colorectal neoplasms, the desmoplastic response, or change in matrix materials such as collagen and elastin, also aids pathologists in the interpretation of neoplastic processes, particularly regarding the presence or absence of invasion in colorectal adenocarcinoma. 34,48 Additionally, disruption of the metabolic cycle in neoplastic cells can result in changes in FAD and NADH concentrations.…”

Section: Unmixing Images By Library Componentsmentioning

confidence: 99%

Identifying molecular contributors to autofluorescence of neoplastic and normal colon sections using excitation-scanning hyperspectral imaging

et al. 2018

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Autofluorescence, the endogenous fluorescence present in cells and tissues, has historically been considered a nuisance in biomedical imaging. Many endogenous fluorophores, specifically, collagen, elastin, nicotinamide adenine dinucleotide, and flavin adenine dinucleotide (FAD), are found throughout the human body. In fluorescence imaging scenarios, these signals can be prohibitive as they can outcompete signals introduced for diagnostic purposes. However, autofluorescence also contains information that has diagnostic value. Recent advances in hyperspectral imaging have allowed the acquisition of significantly more data in a shorter time period by scanning the excitation spectra of fluorophores. The reduced acquisition time and increased signal-to-noise ratio allow for separation of significantly more fluorophores than previously possible. We propose to utilize excitation-scanning hyperspectral imaging of autofluorescence to differentiate neoplastic lesions from surrounding non-neoplastic "normal" tissue. The spectra of isolated autofluorescent molecules are obtained using a custom inverted microscope (TE-2000, Nikon Instruments) with an Xe arc lamp and thin-film tunable filter array (VersaChrome, Semrock, Inc.). Scans utilize excitation wavelengths from 360 to 550 nm in 5-nm increments. The resultant molecule-specific spectra are used to analyze hyperspectral image stacks from normal and neoplastic colorectal tissues. Due to a limited number of samples, neoplastic tissues examined here are a pool of both colorectal adenocarcinoma and adenomatous polyps. The hyperspectral images are analyzed with ENVI software and custom MATLAB scripts, including linear spectral unmixing. Initial results indicate the ability to separate signals of endogenous fluorophores and measure the relative concentrations of fluorophores among healthy and diseased states, in this case, normal colon versus neoplastic colon. These results suggest pathology-specific changes to endogenous fluorophores can be detected using excitation-scanning hyperspectral imaging. Future work will focus on expanding the library of pure molecules, exploring histogram distance metrics as a means for identifying deviations in spectral signatures, and examining more defined disease states.

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Protein phosphatase 2A regulation of markers of extracellular matrix remodelling in hepatocellular carcinoma cells: functional consequences for tumour invasion

Cited by 22 publications

References 64 publications

Protein phosphatase 2A regulates the p38 signaling pathway to affect the migration of astrocytes

Protein phosphatase 2A regulates the p38 signaling pathway to affect the migration of astrocytes

Nicotinic ACh receptor α7 inhibits PDGF‐induced migration of vascular smooth muscle cells by activating mitochondrial deacetylase sirtuin 3

Identifying molecular contributors to autofluorescence of neoplastic and normal colon sections using excitation-scanning hyperspectral imaging

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