U0126 / Promega - LARVOL DELTA

HDGF promotes gefitinib resistance by activating the PI3K/AKT and MEK/ERK signaling pathways in non-small cell lung cancer (Nature, Cell Death Discov) - "The effects of HDGF on promoting the gefitinib resistance were largely attenuated by MK2206 (Akt inhibitor) or U0126 (ERK inhibitor). Mechanistically, gefitinib treatment provoked HDGF expression and activated the Akt and ERK pathways, which were independent of EGFR phosphorylation."

Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer

HDGF promotes gefitinib resistance by activating the PI3K/AKT and MEK/ERK signaling pathways in non-small cell lung cancer (Nature, Cell Death Discov) - "The effects of HDGF on promoting the gefitinib resistance were largely attenuated by MK2206 (Akt inhibitor) or U0126 (ERK inhibitor). Mechanistically, gefitinib treatment provoked HDGF expression and activated the Akt and ERK pathways, which were independent of EGFR phosphorylation."

Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer

[VIRTUAL] Activation of the ERK Pathway Drives Acquired Resistance to Venetoclax in MM Cell Models (ASH 2020) - "We indeed observe a significant increase in the anti-apoptotic proteins MCL1 and BCL-XL in DTEP clones, which translated in our observation of improved sensitivity to MCL1 and BCL-xL inhibitors (S63845 and A-1155463 respectively)...Western blot analysis confirmed activation of ERK and the downstream target cAMP response element-binding (CREB) gene in resistant clones; and importantly treatment with the ERK inhibitor U0126 rescued the resistance to Venetoclax, providing a synergistic activity in resistant clones but not in parental cells, with decreased cell viability and increased apoptotic cell death...In conclusion, we here provide evidences of molecular mechanisms of acquired resistance to Venetoclax with activation of the ERK pathway as one of the prime targets. Combining Venetoclax with ERK inhibitor may therefore prevent or overcome the acquired resistance to Venetoclax observed in MM patients."

IO Biomarker • Preclinical • Hematological Malignancies • Multiple Myeloma • Oncology • BCL2 • BCL2L1 • G0S2 • IGH • MCL1

Unilateral Nephrectomy Stimulates ERK and Is Associated With Enhanced Na Transport. (PubMed, Front Physiol) - "Murine PCs (mpkCCD) were grown on semi-permeable supports under static, FSS, and FSS with U0126 (a MEK1/2 inhibitor) conditions to measure the effects of FSS and ERK inhibition on amiloride sensitive Na short circuit current (Isc). In conclusion, pERK increases in whole kidney and, specifically, CCD cells after nephrectomy, but pERK was not associated with active proliferation at 1-month post-nephrectomy. In vitro studies suggest high tubular flow induces ERK dependent ENaC Na absorption and may play a critical role in Na balance post-nephrectomy."

Journal • Renal Disease

Elucidating the cellular mechanism for E2-induced dermal fibrosis. (PubMed, Arthritis Res Ther) - "We conclude that E2-induced dermal fibrosis occurs in part through induction of TGFβ1, 2, and Col22A1, which is regulated through EGR1 and the MAPK pathway. Thus, blocking estrogen signaling and/or production may be a novel therapeutic option in pro-fibrotic diseases."

Journal • Fibrosis • Immunology • Rheumatology • Scleroderma • Systemic Sclerosis • EGR1 • ER

High glucose induces Drp1-mediated mitochondrial fission via the Orai1 calcium channel to participate in diabetic cardiomyocyte hypertrophy. (PubMed, Cell Death Dis) - "In addition, the CnA inhibitor cyclosporin A and p-ERK1/2 inhibitor U0126 improved HG-induced cardiomyocyte hypertrophy by promoting and inhibiting phosphorylation of Drp1 at S637 and S616, respectively. In summary, we identified Drp1 as a downstream target of Orai1-mediated Ca entry, via activation by p-ERK1/2-mediated phosphorylation at S616 or CnA-mediated dephosphorylation at S637 in DCM. Thus, the Orai1-Drp1 axis is a novel target for treating DCM."

Journal • Cardiomyopathy • Cardiovascular • Diabetes • Metabolic Disorders

Mex3a promotes oncogenesis through the RAP1/MAPK signaling pathway in colorectal cancer and is inhibited by hsa-miR-6887-3p. (PubMed, Cancer Commun (Lond)) - "Our study demonstrated that the hsa-miR-6887-3p/Mex3a/RAP1GAP signaling axis was a key regulator of CRC and Mex3a has the potential to be a new diagnostic marker and treatment target for CRC."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • HIF1A • PCR

Isobavachalcone inhibits acute myeloid leukemia: Potential role for ROS-dependent mitochondrial apoptosis and differentiation. (PubMed, Phytother Res) - "Furthermore, IBC obviously promoted the differentiation of AML cells, accompanied by the increase of the phosphorylation of MEK and ERK and the C/EBPα expression as well as the C/EBPβ LAP/LIP isoform ratio, which was significantly reversed by U0126, a specific inhibitor of MEK...In addition, IBC also exhibited an obvious anti-AML effect in NOD/SCID mice with the engraftment of HL-60 cells. Together, our study suggests that the ROS-medicated signaling pathway is highly involved in IBC-induced apoptosis and differentiation of AML cells."

IO biomarker • Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2 • BCL2L1 • CASP3 • CASP9 • MCL1 • PARP1

[VIRTUAL] REGULATION OF FGF2-INDUCED CELL PROLIFERATION BY INHIBITORY GPCR IN NORMAL PITUITARY CELL (ICE 2021) - " Anterior pituitary primary cell cultures from Wistar female rats were treated with FGF2 (10ng/mL) or somatostatin analogue (OCT, 100nM) alone or co-incubated with or without an inhibitor of GPCR-Gαi, pertussis toxin (PTX, 500nM) or MEK inhibitor (U0126, 100µM)... These results show that the FGF2 and OCT combined treatment induced a decreased of prolactin and somatotroph population associated with G1-phase arrest, modulating key proteins in the early phases (transition from G0/G1 to the S-phase) of cell cycle progression and proteins involved in the cell proliferation. This regulatory effect, mediated for GPCR-Gαi, could participate in the homeostasis of lactotroph and somatotroph in phycological conditions"

Infectious Disease • Respiratory Diseases • CCND1 • CCNE1 • CDK4 • CDKN1A • FGF2

Prolonged arsenic exposure increases tau phosphorylation in differentiated SH-SY5Y cells: The contribution of GSK3 and ERK1/2. (PubMed, Environ Toxicol Pharmacol) - "Additionally, sodium arsenite increased levels of active phosphorylation of ERK1/2, and inhibition of ERK1/2 by U0126 partially improved the Tau1 reduction...These results suggest that arsenic induces tau hyperphosphorylation in the membrane fraction which may lead to its redistribution from the membrane fraction to the cytosol, where it promotes neurofibrillary formation. Collectively, we demonstrate that prolonged arsenic exposure increases tau phosphorylation, partly through GSK3 and ERK1/2 activation, and insoluble tau aggregates, hence possibly contributing to the development of sporadic AD."

Journal • Alzheimer's Disease • CNS Disorders • Neuroblastoma • Oncology • Solid Tumor • GSK3B

WDPCP Modulates Cilia Beating Through the MAPK/ERK Pathway in Chronic Rhinosinusitis With Nasal Polyps. (PubMed, Front Cell Dev Biol) - "The mitochondrial dysfunction caused by U0126 or lacking WDPCP could be partially recovered by dexamethasone. The low expression of WDPCP in nasal epithelium could affect mitochondria via the MAPK/ERK pathway, which may contribute to the dysfunction in the beating of cilia in CRSwNP."

Journal • Chronic Rhinosinusitis With Nasal Polyps • Immunology • Metabolic Disorders • Nasal Polyps • Otorhinolaryngology • Respiratory Diseases • Sinusitis

PELP1 promotes the expression of RUNX2 via the ERK pathway during the osteogenic differentiation of human periodontal ligament stem cells. (PubMed, Arch Oral Biol) - "PELP1 regulates the expression of RUNX2 during the osteogenic differentiation of hPDLSCs and that the ERK pathway is involved in this process."

Journal • PELP1

5-aza-2'-deoxycytidine may regulate the inflammatory response of human odontoblast-like cells through the NF-κB pathway. (PubMed, Int Endod J) - "AZA regulated the LTA-induced inflammatory response through NF-κB signal pathway in hOBs. This study highlights the important role of DNA methylation in the immunity defense of odontoblasts during the dental pulp immunity response to caries."

Journal • Immunology • Inflammation • CXCL8 • IL6 • MYD88 • TNFA

Pharmacological Protein Kinase C Modulators Reveal a Pro-hypertrophic Role for Novel Protein Kinase C Isoforms in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes. (PubMed, Front Pharmacol) - "The mitogen-activated kinase kinase 1/2 inhibitor U0126 inhibited PKC agonist-induced hypertrophy fully and ET-1-induced hypertrophy partially...This pro-hypertrophic effect of PKC activators should be considered when developing PKC-targeted compounds for e.g. cancer or Alzheimer's disease. Furthermore, this study provides further evidence on distinct PKC-independent mechanisms of ET-1-induced hypertrophy both in NRVMs and hiPSC-CMs."

Journal • Alzheimer's Disease • Cardiovascular • CNS Disorders • Congestive Heart Failure • Heart Failure • Oncology • EDN1

Molecular imaging of the kinetics of hyperactivated ERK1/2-mediated autophagy during acquirement of chemoresistance. (PubMed, Cell Death Dis) - "Utilizing indigenously developed cisplatin-paclitaxel-resistant models of ovarian cancer cells, we report an intriguing oscillation in chemotherapy-induced autophagic flux across stages of resistance, which was found to be specifically elevated at the early stages or onset of chemoresistance...This increased flux at early stages of resistance was found to be dictated by a hyperactive ERK1/2 signaling, which when inhibited either pharmacologically (U0126/Trametinib) or genetically, reduced p62 degradation, number of LC3LAMP1 puncta, autophagolysosome formation, and led to chemo-sensitization and apoptosis...Noninvasive imaging of autophagic flux using a novel autophagy sensor (mtFL-p62 fusion reporter) showed that combinatorial treatment of platinum-taxol along with Trametinib/chloroquine blocked autophagic flux in live cells and tumor xenografts...This is probably the first report of real-time monitoring of chemotherapy-induced autophagy kinetics through noninvasive..."

Journal • Oncology • Ovarian Cancer • Solid Tumor

Efficient iron utilization compensates for loss of extracellular matrix of ovarian cancer spheroids. (PubMed, Free Radic Biol Med) - "Impairment of autophagy by U0126 or Olaparib results in lysosomal iron accumulation and decrease of the cytosolic labile iron pool, leading to reduction of SCD1, lipid level and cell viability. Our findings reveal that ovarian cancer spheroids develop efficient iron utilization system to survive. Targeting iron utilization in ovarian cancer spheroids may have the potential to become new treatment strategies for ovarian cancer metastasis."

Journal • Metabolic Disorders • Oncology • Ovarian Cancer • Solid Tumor • TFRC

PLAU directs conversion of fibroblasts to inflammatory cancer-associated fibroblasts, promoting esophageal squamous cell carcinoma progression via uPAR/Akt/NF-κB/IL8 pathway. (PubMed, Cell Death Discov) - "Through loss-of function and gain-of function experiments, we found that PLAU promoted ESCC proliferation and clone formation via MAPK pathway, and promotes migration by upregulating Slug and MMP9, which can be reversed by the MEK 1/2 inhibitor U0126...The IL8 secreted by CAFs in turn promotes the high expression of PLAU in tumor cells and further promoted the progression of ESCC. In summary, PLAU was not only a prognostic marker of ESCC, which promoted tumor cell proliferation and migration, but also promoted the formation of inflammatory CAFs by the PLAU secreted by tumor cells."

Journal • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Oncology • Squamous Cell Carcinoma • CAFs • CXCL8 • MAP2K1 • MMP9

U0126 pretreatment inhibits cisplatin-induced apoptosis and autophagy in HEI-OC1 cells and cochlear hair cells. (PubMed, Toxicol Appl Pharmacol) - "In addition, U0126 reduced the cisplatin-induced production of reactive oxygen species as well as the cisplatin-induced decrease in the mitochondrial membrane potential. These findings suggest that U0126 may be a potential therapeutic candidate for the prevention of cisplatin-induced ototoxicity."

Journal • Cardiovascular • Ischemic stroke • Oncology • Otorhinolaryngology

AKAP2 overexpression modulates growth plate chondrocyte functions through ERK1/2 signaling. (PubMed, Bone) - "More importantly, the promotive effects of AKAP2 overexpression on GPC proliferation, differentiation, and ECM synthesis were significantly reversed by the ERK1/2 signaling antagonist U0126, suggesting that AKAP2 enhances GPC functions through ERK1/2 signaling. In conclusion, we demonstrate AKAP2 overexpression-induced enhancement of GPC functions through ERK1/2 signaling. Considering the critical role of GPC functions in adolescent idiopathic scoliosis (AIS) pathogenesis, the application of AKAP2 targeting in AIS treatment should be investigated in future studies."

Journal

L20, a Calothrixin B analog, induces intrinsic apoptosis on HEL cells through ROS/γ-H2AX/p38 MAPK pathway. (PubMed, Biomed Pharmacother) - "Pretreatment with P38/ERK inhibitors, SB203580, and U0126, decreased L20-induced apoptosis. These findings indicated that L20 induced mitochondrial mediated-apoptosis and G/M arrest through DNA damage and modulation of p38 MAPK pathways. Thus, the study suggests L20, a chemical analog of Calothrixin B, as a novel chemotherapeutic agent against erythroleukemia."

Journal • Hematological Malignancies • Leukemia • Oncology

ERK-Directed Phosphorylation of mGlu5 Gates Methamphetamine Reward and Reinforcement in Mouse. (PubMed, Int J Mol Sci) - "We confirmed the functional relevance for mPFC ERK activation for MA-induced place-preference via site-directed infusion of the MEK inhibitor U0126. Through studies of transgenic mice with alanine point mutations on T1123/S1126 of mGlu5 that disrupt ERK-dependent phosphorylation of the receptor, we discovered that ERK-dependent mGlu5 phosphorylation normally suppresses MA-induced conditioned place-preference (MA-CPP), but is necessary for this drug's reinforcing properties. If relevant to humans, the present results implicate individual differences in the capacity of MA-associated cues/contexts to hyper-activate ERK signaling within mPFC in MA Use Disorder vulnerability and pose mGlu5 as one ERK-directed target contributing to the propensity to seek out and take MA."

Journal • CNS Disorders • Psychiatry • MAPK1

Sorafenib not only impairs endothelium-dependent relaxation but also promotes vasoconstriction through the upregulation of vasoconstrictive endothelin type B receptors. (PubMed, Toxicol Appl Pharmacol) - "To elucidate the underlying mechanism, rat mesenteric arteries were subjected to organ cultured in the presence of different concentrations of sorafenib (0, 3, 6 and 9 mg/L) with or without inhibitors (U0126, 10 M; SB203580, 10 M; SP200126, 10 M) of MAPK kinases, and then acetylcholine- or sodium nitroprusside-induced vasodilation and sarafotoxin 6c-induced vasoconstriction were monitored by a sensitive myograph. Furthermore, it was observed that the oral administration of sorafenib caused an increase in blood pressure and plasma ET-1, upregulation of the ET receptor and the activation of JNK in the mesenteric arteries. In conclusion, sorafenib not only impairs endothelium-dependent vasodilatation but also enhances ET receptor-mediated vasoconstriction, which may be the casual factors for hypertension and other adverse vascular effects in patients treated with sorafenib."

Journal • Hypertension • Oncology • Solid Tumor • CD31 • NOS3

Alendronate promotes the gene expression of extracellular matrix mediated by SP-1/SOX-9. (PubMed, Hum Exp Toxicol) - "Notably, Alendronate increased the phosphorylation of ERK1/2 and inhibition of ERK1/2 using its specific inhibitor U0126 blocked the expression of SP-1. Finally, we found that treatment with Alendronate could rescue TNF-α-induced reduction of Col2α1, COL9α2, Acan and SOX-9. Our data indicated that Alendronate might promote the gene expression of extracellular matrix through SOX-9 mediated by the ERK1/2/SP1 signaling pathway."

Journal • Immunology • Osteoarthritis • Pain • Rheumatology • TNFA

Stromal cell-derived factor-1/Exendin-4 cotherapy facilitates the proliferation, migration and osteogenic differentiation of human periodontal ligament stem cells in vitro and promotes periodontal bone regeneration in vivo. (PubMed, Cell Prolif) - "SDF-1/EX-4 cotherapy synergistically regulated PDLSC activities, promoted periodontal bone formation, thereby providing a new strategy for periodontal bone regeneration."

Journal • Preclinical • CD34 • CXCL12 • CXCR4

Phosphorylation of Specificity protein 3 is critical for activation of β4-galactosyltransferase 3 gene promoter in SH-SY5Y human neuroblastoma cell line. (PubMed, Biol Pharm Bull) - "Meanwhile, the treatment with U0126, an inhibitor for MAPK kinase, decreased the MAPK signaling and the promoter activity...The results suggest that the phosphorylation of these Ser residues is implicated in the promoter activation by Sp3. This study demonstrates that the phosphorylation of Sp3 plays important roles in the transcriptional activation of the β4GalT3 gene in human neuroblastoma."

Journal • Preclinical • Neuroblastoma • Oncology • Solid Tumor