scholarly journals P38 MAPK Promotes Migration and Metastatic Activity of BRAF Mutant Melanoma Cells by Inducing Degradation of PMCA4b

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1209
Author(s):  
Randa Naffa ◽  
Lisa Vogel ◽  
Luca Hegedűs ◽  
Katalin Pászty ◽  
Sarolta Tóth ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Mapk Pathway ◽  
Melanoma Cells ◽  
Cell System ◽  
Metastasis Suppressor ◽  
Melanoma Metastasis ◽  
P38 Mapk Pathway ◽  
Metastatic Activity ◽  
Braf Mutant

Metastatic melanoma is the most aggressive type of skin cancer. Previously, we identified the plasma membrane Ca2+ pump isoform 4b (PMCA4b or ATP2B4) as a putative metastasis suppressor in BRAF mutant melanoma cells. Metastasis suppressors are often downregulated in cancer, therefore, it is important to identify the pathways involved in their degradation. Here, we studied the role of p38 MAPK in PMCA4b degradation and its effect on melanoma metastasis. We found that activation of p38 MAPK induces internalization and subsequent degradation of PMCA4b through the endo/lysosomal system that contributes to the low PMCA4b steady-state protein level of BRAF mutant melanoma cells. Moreover, BRAF wild type cell models including a doxycycline-inducible HEK cell system revealed that p38 MAPK is a universal modulator of PMCA4b endocytosis. Inhibition of the p38 MAPK pathway markedly reduced migration, colony formation and metastatic activity of BRAF mutant cells in vitro partially through an increase in PMCA4b and a decrease in β4 integrin abundance. In conclusion, our data suggest that the p38 MAPK pathway plays a key role in PMCA4b degradation and inhibition of this pathway—by increasing the stability of PMCA4b—may provide a potential therapeutic target for inhibition of melanoma progression and metastasis.

Tougu Xiaotong capsules may inhibit p38 MAPK pathway-mediated inflammation: In vivo and in vitro verification

2020 ◽  
Vol 249 ◽  
pp. 112390 ◽  
Author(s):  
Xihai Li ◽  
Zhenli Zhang ◽  
Wenna Liang ◽  
Jianwei Zeng ◽  
Xiang Shao ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Mapk Pathway ◽  
P38 Mapk Pathway

Sema4C participates in myogenic differentiation in vivo and in vitro through the p38 MAPK pathway

2007 ◽  
Vol 86 (6) ◽  
pp. 331-344 ◽  
Author(s):  
Haitao Wu ◽  
Xuan Wang ◽  
Shuhong Liu ◽  
Yan Wu ◽  
Tong Zhao ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Mapk Pathway ◽  
Myogenic Differentiation ◽  
P38 Mapk Pathway

Activation of TAO2 Kinase by Arsenic Trioxide in Leukemic Cells

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5324-5324
Author(s):  
Jennifer L. McNeer ◽  
Blazej Dolniak ◽  
Barbara Kroczynska ◽  
Antonella Sassano ◽  
Leonidas Platanias
Keyword(s):  
Arsenic Trioxide ◽  
P38 Mapk ◽  
Mapk Pathway ◽  
Leukemic Cell ◽  
Buthionine Sulfoximine ◽  
P38 Map Kinase ◽  
Leukemic Cells ◽  
Kinase Assay ◽  
P38 Mapk Pathway

Abstract Arsenic Trioxide (As2O3) has major efficacy in the treatment of acute promyelocytic leukemia (APL), but its use in other malignancies is limited by the need for high intracellular concentrations to induce apoptosis. Prior work in our laboratory has demonstrated that the p38 MAP kinase (MAPK) pathway is activated following treatment of cells with As2O3 and exhibits negative regulatory effects on As2O3-induced apoptosis and growth suppression. In the current study, we sought to identify upstream effector mechanisms by which the p38 pathway is activated by As2O3 in leukemic cells. We found that the MAPK kinase kinase TAO2 (thousand and one amino acid protein kinase 2) is phosphorylated on Ser181 after treatment of NB4, NB4.306, and U937 cells with arsenic. Such phosphorylation was rapid, occurring as early as after 5 minutes of As2O3 treatment. In addition, our data indicate that such phosphorylation occurs downstream of As2O3-induced redox reactions, as demonstrated by increased phosphorylation in cells pretreated with the oxidizing agent buthionine sulfoximine (BSO) and decreased phosphorylation following pretreatment with the reducing agent dithiothreitol (DTT). Arsenic treatment of the cells also resulted in activation of the kinase domain of TAO2, as evidenced in in vitro kinase assay studies using ATF2 as an exogenous substrate. siRNA-mediated TAO2 knockdown resulted in inhibition of As2O3-induced p38 phosphorylation, suggesting that this kinase acts as an upstream effector of the arsenic-activated p38 MAPK pathway. Moreover, in studies to determine the functional relevance of TAO2 in the induction of As2O3-dependent antileukemic responses we found that siRNA-mediated TAO2 knockdown enhanced the suppressive effects of As2O3 on KT1-derived leukemic progenitor (CFU-L) growth in clonogenic assays in methylcellulose. Altogether, our data demonstrate that TAO2 is activated during arsenic treatment of leukemic cells lines and acts as an upstream activator of the p38 MAPK pathway. Such activation appears to occur in a negative feedback regulatory manner to compensate for the suppressive effects of As2O3 on leukemic cell growth. Importantly, these findings raise the possibility that targeting TAO2 may provide a novel approach to enhance the generation of the antileukemic properties of As2O3.

scholarly journals Nephroprotective Effects of N-Acetylcysteine Amide against Contrast-Induced Nephropathy through Upregulating Thioredoxin-1, Inhibiting ASK1/p38MAPK Pathway, and Suppressing Oxidative Stress and Apoptosis in Rats

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Xuezhong Gong ◽  
Yiru Duan ◽  
Junli Zheng ◽  
Yiquan Wang ◽  
Guohua Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
P38 Mapk ◽  
Mapk Pathway ◽  
Contrast Induced Nephropathy ◽  
Tubular Cells ◽  
Renal Tubular Cells ◽  
P38 Mapk Pathway ◽  
Thioredoxin 1 ◽  
Renal Tubular

Contrast-induced nephropathy (CIN) is a leading cause of hospital-acquired acute kidney injury (AKI) due to apoptosis induced in renal tubular cells. Our previous study demonstrated the novel N-acetylcysteine amide (NACA); the amide form of N-acetyl cysteine (NAC) prevented renal tubular cells from contrast-induced apoptosis through inhibiting p38 MAPK pathway in vitro. In the present study, we aimed to compare the efficacies of NACA and NAC in preventing CIN in a well-established rat model and investigate whether thioredoxin-1 (Trx1) and apoptosis signal-regulating kinase 1 (ASK1) act as the potential activator for p38 MAPK. NACA significantly attenuated elevations of serum creatinine, blood urea nitrogen, and biomarkers of AKI. At equimolar concentration, NACA was more effective than NAC in reducing histological changes of renal tubular injuries. NACA attenuated activation of p38 MAPK signal, reduced oxidative stress, and diminished apoptosis. Furthermore, we demonstrated that contrast exposure resulted in Trx1 downregulation and increased ASK1/p38 MAPK phosphorylation, which could be reversed by NACA and NAC. To our knowledge, this is the first report that Trx1 and ASK1 are involved in CIN. Our study highlights a renal protective role of NACA against CIN through modulating Trx1 and ASK1/p38 MAPK pathway to result in the inhibition of apoptosis among renal cells.

scholarly journals Glibenclamide–sulfonylurea receptor 1 antagonist alleviates LPS-induced BV2 cell activation through the p38/MAPK pathway

RSC Advances ◽  
2017 ◽  
Vol 7 (44) ◽  
pp. 27206-27213 ◽  
Author(s):  
Zhiming Xu ◽  
Yingliang Liu ◽  
Dianxu Yang ◽  
Fang Yuan ◽  
Jun Ding ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Microglial Activation ◽  
Cell Activation ◽  
Mapk Pathway ◽  
Sulfonylurea Receptor ◽  
P38 Mapk Pathway ◽  
Sulfonylurea Receptor 1

We investigated the anti-neuroinflammatory activity and mechanism of glibenclamide, sulfonylurea receptor 1 (Sur1) antagonist, against LPS-induced microglial activationin vitro.

scholarly journals Data on Tougu Xiaotong capsules may inhibit p38 MAPK pathway-mediated inflammation in vitro

Data in Brief ◽  
2020 ◽  
Vol 28 ◽  
pp. 105023 ◽  
Author(s):  
Xihai Li ◽  
Zhenli Zhang ◽  
Wenna Liang ◽  
Jianwei Zeng ◽  
Xiang Shao ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Mapk Pathway ◽  
P38 Mapk Pathway

scholarly journals FR167653 inhibits fibronectin expression and apoptosis in diabetic glomeruli and in high-glucose-stimulated mesangial cells

2008 ◽  
Vol 295 (2) ◽  
pp. F595-F604 ◽  
Author(s):  
Dong-Sub Jung ◽  
Jin Ji Li ◽  
Seung-Jae Kwak ◽  
Sun Ha Lee ◽  
Jehyun Park ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Protein Expression ◽  
P38 Mapk ◽  
High Glucose ◽  
Mesangial Cells ◽  
Mapk Pathway ◽  
P38 Mapk Pathway ◽  
Fibronectin Expression

Previous in vitro studies suggest that the p38 MAPK pathway may be involved in the pathogenesis of diabetic nephropathy, but the consequences of the inhibition of the p38 MAPK pathway have not been well elucidated in diabetic (DM) glomeruli. This study was undertaken to investigate the effect of p38 MAPK inhibitor, FR167653, on fibronectin expression and apoptosis in DM glomeruli and in high-glucose-stimulated mesangial cells (MC). In vivo, 32 Sprague-Dawley rats were injected with diluent (control, N = 16) or streptozotocin intraperitoneally (DM, N = 16). Eight rats from each group were treated with FR167653 for 3 mo. In vitro, rat MC were exposed to medium containing 5.6 mM glucose or 30 mM glucose [high glucose (HG)] with or without 10−6 M FR167653 for 24 h. Fibronectin mRNA and protein expression were determined by real-time PCR and Western blot, respectively. Western blot for apoptosis-related molecules, terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling assay, and Hoechst 33342 staining were performed to determine apoptosis. FR167653 ameliorated the increases in fibronectin-to-GAPDH mRNA ratio and protein expression in DM glomeruli by 89 and 79% and in HG-stimulated MC by 70 and 91%, respectively ( P < 0.05). Under diabetic conditions, Bcl-2 protein expression was decreased, whereas cleaved caspase-3 protein expression was increased ( P < 0.05), and these changes were inhibited by FR167653 treatment. Apoptotic cells were also significantly increased in DM glomeruli and in HG-stimulated MC ( P < 0.05), and FR167653 ameliorated these increases in apoptotic cells, both in vivo and in vitro. In conclusion, these findings suggest that the inhibition of the p38 MAPK pathway has a beneficial effect on the development of diabetic nephropathy by inhibiting the increase in fibronectin expression and apoptosis.

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