scholarly journals Synthetic Optimization and MAPK Pathway Activation Anticancer Mechanism of Polyisoprenylated Cysteinyl Amide Inhibitors

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5757
Author(s):  
Nada Tawfeeq ◽  
Yonghao Jin ◽  
Nazarius S. Lamango
Keyword(s):  
Mapk Pathway ◽  
A549 Cells ◽  
Mapk Signaling ◽  
Protein Signaling ◽  
Ras Gtpases ◽  
Anticancer Effects ◽  
Pathway Activation ◽  
Significant Difference ◽  
Signaling Axis ◽  
Anticancer Mechanism

Abnormalities of the MAPK pathway play vital roles in cancer initiation and progression. RAS GTPases that are key upstream mediators of the pathway are mutated in 30% of human cancers. Polyisoprenylated cysteinyl amide inhibitors (PCAIs) were designed as potential targeted therapies against the RAS-driven cancers. The current study reports on the optimization of the PCAIs and the determination of their mechanisms of action in KRAS-mutant cancer cells. They display ClogP values ranging from 3.01 to 6.35, suppressing the viabilities of KRAS-mutant MDA-MB-231, A549, MIA PaCa-2, and NCI-H1299 cells in 2D and 3D cultures with EC50 values of 2.2 to 6.8, 2.2 to 7.6, 2.3 to 6.5 and 5.0 to 14 µM, respectively. When A549 cells were treated with the PCAIs, NSL-YHJ-2-27, for 48 h, no significant difference was observed in the levels of total or phosphorylated B- and C-Raf proteins. However, at 5 µM, it stimulated the phosphorylation of MEK1/2, ERK1/2, and p90RSK by 84%, 59%, and 160%, respectively, relative to controls. A non-farnesylated analog, NSL-YHJ-2-62, did not elicit similar effects. These data reveal that effects on the RAS-MAPK signaling axis most likely contribute to the anticancer effects of the PCAIs, possibly through the proapoptotic isoforms of p90RSK. The PCAIs may thus have the potential to serve the unmet therapeutic needs of patients with aberrant hyperactive G-protein signaling.

Long non-coding RNA H19 acts as a microRNA-194 sponge to inhibit the apoptosis and promote the proliferation of hypertrophic scar fibroblasts

2021 ◽  
Author(s):  
Bo Liu ◽  
Lijuan Lin ◽  
Shengjin Yu ◽  
Rongjun Xia ◽  
Linlin Zheng
Keyword(s):  
P38 Mapk ◽  
Hypertrophic Scar ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Hypertrophic Scars ◽  
Downstream Effector ◽  
Non Coding Rna ◽  
Proliferation And Apoptosis ◽  
Signaling Axis ◽  
Underlying Mechanisms

The effects of long non-coding RNAs (lncRNAs) on the proliferation of hypertrophic scars have been described. However, the underlying mechanisms are not well characterized. The present study aimed to investigate the mechanisms of lncRNA H19 in hypertrophic scars. The effects of the lncRNA H19 on the proliferation and apoptosis of hypertrophic scar fibroblasts (HSFs) were analyzed using 5’-Ethynyl-2’-deoxyuridine staining, flow cytometry, and MTT. The results revealed H19 promoted the proliferation and inhibited the apoptosis in HSF. In addition, the binding associations between H19 and microRNA-194 (miR-194), and miR-194 and insulin-like growth factor-I receptor (IGF1R) were identified using bioinformatics screening and verified using dual-luciferase assays. Furthermore, the effects of the IGF1R knockdown on H19-induced HSF phenotypes and regulation over the p38 MAPK pathway were determined. Mechanistically, miR-194 was identified as the downstream effector of the H19-mediated phenotypes of HSFs through its ability to directly target IGF1R, thus modulating the p38 MAPK signaling pathway. In conclusion, the findings suggested that H19 may inhibit the apoptosis and promote the proliferation of HSFs through the miR-194/IGF1R/p38 MAPK signaling axis, thereby contributing to the progression of hypertrophic scars. These findings may provide novel targets for the treatment of hypertrophic scars.

scholarly journals p27kip1 controls H-Ras/MAPK activation and cell cycle entry via modulation of MT stability

2015 ◽  
Vol 112 (45) ◽  
pp. 13916-13921 ◽  
Author(s):  
Linda Fabris ◽  
Stefania Berton ◽  
Ilenia Pellizzari ◽  
Ilenia Segatto ◽  
Sara D’Andrea ◽  
...  
Keyword(s):  
Phase Transition ◽  
Cell Cycle ◽  
Signaling Pathway ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
S Phase ◽  
Point Of View ◽  
Cell Cycle Entry ◽  
Pathway Activation ◽  
Direct Binding

The cyclin-dependent kinase (CDK) inhibitor p27kip1 is a critical regulator of the G1/S-phase transition of the cell cycle and also regulates microtubule (MT) stability. This latter function is exerted by modulating the activity of stathmin, an MT-destabilizing protein, and by direct binding to MTs. We recently demonstrated that increased proliferation in p27kip1-null mice is reverted by concomitant deletion of stathmin in p27kip1/stathmin double-KO mice, suggesting that a CDK-independent function of p27kip1 contributes to the control of cell proliferation. Whether the regulation of MT stability by p27kip1 impinges on signaling pathway activation and contributes to the decision to enter the cell cycle is largely unknown. Here, we report that faster cell cycle entry of p27kip1-null cells was impaired by the concomitant deletion of stathmin. Using gene expression profiling coupled with bioinformatic analyses, we show that p27kip1 and stathmin conjunctly control activation of the MAPK pathway. From a molecular point of view, we observed that p27kip1, by controlling MT stability, impinges on H-Ras trafficking and ubiquitination levels, eventually restraining its full activation. Our study identifies a regulatory axis controlling the G1/S-phase transition, relying on the regulation of MT stability by p27kip1 and finely controlling the spatiotemporal activation of the Ras-MAPK signaling pathway.

scholarly journals Extracellular signal-regulated kinase mediates chromatin rewiring and lineage transformation in lung cancer

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Yusuke Inoue ◽  
Ana Nikolic ◽  
Dylan Farnsworth ◽  
Rocky Shi ◽  
Fraser D Johnson ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Mapk Pathway ◽  
Neuroendocrine Differentiation ◽  
Therapy Resistance ◽  
Mapk Signaling ◽  
Chromatin Accessibility ◽  
Extracellular Signal Regulated Kinase ◽  
Pathway Activation ◽  
Extracellular Signal ◽  
Ets Factors

Small-cell lung cancer (SCLC) is neuroendocrine in origin and rarely contains mutations in the MAPK pathway. Likewise, non-SCLC (NSCLC) that transform to SCLC concomitantly with development of therapy resistance downregulate MAPK signaling, suggesting an inverse relationship between pathway activation and lineage state. To test this, we activated MAPK in SCLC through expression of mutant KRAS or EGFR, which revealed suppression of the neuroendocrine differentiation via ERK. We found that ERK induces expression of ETS factors that mediate transformation into a NSCLC-like state. ATAC-seq demonstrated ERK-driven changes in chromatin accessibility at putative regulatory regions and global chromatin rewiring at neuroendocrine and ETS transcriptional targets. Further, induction of ETS factors and suppression of neuroendocrine differentiation were dependent on histone acetyltransferases CBP/p300. Overall, we describe how the ERK-CBP/p300-ETS axis promotes a lineage shift between neuroendocrine and non-neuroendocrine phenotypes and provide rationale for the disruption of this program during transformation-driven resistance to targeted therapy.

scholarly journals Osteopontin expression and its relationship with prognostic biomarkers in canine mammary carcinomas

2020 ◽  
Vol 40 (3) ◽  
pp. 210-219
Author(s):  
Lidianne N. Monteiro ◽  
Breno S. Salgado ◽  
Deilson E. Oliveira ◽  
Luis G. Rivera-Calderon ◽  
Luis M. Montoya-Flórez ◽  
...  
Keyword(s):  
Stromal Cells ◽  
Poor Prognosis ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Her2 Overexpression ◽  
Canine Mammary Tumor ◽  
Mammary Carcinomas ◽  
Osteopontin Expression ◽  
Pathway Activation ◽  
Pathologic Processes

ABSTRACT: Osteopontin is a glycophosphoprotein implicated in different physiologic and pathologic processes and is known to be involved in progression and metastasis of various cancers in humans, but this relation is still little explored in the veterinary. The aim was to evaluate the expression of osteopontin in canine mammary carcinomas and its relation with well-established canine mammary tumor biomarkers. For that, expression of OPN, EGFR, HER2, and c-Kit were evaluated along with Ki67 rate in 43 mammary carcinomas. Osteopontin was demonstrated to be expressed by neoplastic epithelial cells in all carcinomas as well as in stromal cells from the tumor microenvironment. Relation between high osteopontin expression and EGFR positivity (P<0.001) and HER2 overexpression (P=0.012) was demonstrated. In conclusion, high OPN expression seems to be related to poor prognosis and MAPK pathway activation, given the association with EGFR and HER2, members of the MAPK signaling pathway.

scholarly journals A Comprehensive Review on MAPK: A Promising Therapeutic Target in Cancer

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1618 ◽  
Author(s):  
Braicu ◽  
Buse ◽  
Busuioc ◽  
Drula ◽  
Gulei ◽  
...  
Keyword(s):  
Cancer Therapy ◽  
Mapk Pathway ◽  
Alternative Pathway ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Cancer Management ◽  
Pathway Activation ◽  
Promising Therapeutic Target ◽  
Mitogen Activated Protein ◽  
Mapk Inhibitors

The mitogen-activated protein kinase (MAPK) pathway is an important bridge in the switch from extracellular signals to intracellular responses. Alterations of signaling cascades are found in various diseases, including cancer, as a result of genetic and epigenetic changes. Numerous studies focused on both the homeostatic and the pathologic conduct of MAPK signaling; however, there is still much to be deciphered in terms of regulation and action models in both preclinical and clinical research. MAPK has implications in the response to cancer therapy, particularly the activation of the compensatory pathways in response to experimental MAPK inhibition. The present paper discusses new insights into MAPK as a complex cell signaling pathway with roles in the sustenance of cellular normal conduit, response to cancer therapy, and activation of compensatory pathways. Unfortunately, most MAPK inhibitors trigger resistance due to the activation of compensatory feed-back loops in tumor cells and tumor microenvironment components. Therefore, novel combinatorial therapies have to be implemented for cancer management in order to restrict the possibility of alternative pathway activation, as a perspective for developing novel therapies based on integration in translational studies.

scholarly journals Antiprolactinoma Effect of Hordenine by Inhibiting MAPK Signaling Pathway Activation in Rats

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Xiong Wang ◽  
Run-zhu Guo ◽  
Li Ma ◽  
Qiao-yan Ding ◽  
Jun-hua Meng ◽  
...  
Keyword(s):  
Pituitary Gland ◽  
Signaling Pathway ◽  
Mapk Pathway ◽  
Interleukin 1 ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Pathway Activation ◽  
Mitogen Activated Protein ◽  
Jnk Activation

Prolactinomas are harmful to human health, and the clinical first-line treatment drug is bromocriptine. However, 20% prolactinomas patients did not respond to bromocriptine. Hordenine is an alkaloid separated from Fructus Hordei Germinatus, which showed significant antihyperprolactinemia activity in rats. The aim of this study was to explore the effect and mechanism of hordenine on prolactinomas in rats. The study used estradiol to induce prolactinomas, which caused the activation of the pituitary mitogen-activated protein kinase (MAPK) pathway in rats significantly. The treatment of hordenine restored estradiol, induced the overgrowth of pituitary gland, and reduced the prolactin (PRL) accumulation in the serum and pituitary gland of rats by blocking the MAPK (p38, ERK1/2, and JNK) activation and production of inflammatory cytokines, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6). The antiprolactinoma effect of hordenine was mediated by inhibiting the MAPK signaling pathway activation in rats.

scholarly journals A kinome-centered CRISPR-Cas9 screen identifies activated BRAF to modulate enzalutamide resistance with potential therapeutic implications in BRAF-mutated prostate cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sander A. L. Palit ◽  
Jeroen van Dorp ◽  
Daniel Vis ◽  
Cor Lieftink ◽  
Simon Linder ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Clinical Settings ◽  
Therapeutic Implications ◽  
Activating Mutations ◽  
Signaling Axis ◽  
Important Challenge

AbstractResistance to drugs targeting the androgen receptor (AR) signaling axis remains an important challenge in the treatment of prostate cancer patients. Activation of alternative growth pathways is one mechanism used by cancer cells to proliferate despite treatment, conferring drug resistance. Through a kinome-centered CRISPR-Cas9 screen in CWR-R1 prostate cancer cells, we identified activated BRAF signaling as a determinant for enzalutamide resistance. Combined pharmaceutical targeting of AR and MAPK signaling resulted in strong synergistic inhibition of cell proliferation. The association between BRAF activation and enzalutamide resistance was confirmed in two metastatic prostate cancer patients harboring activating mutations in the BRAF gene, as both patients were unresponsive to enzalutamide. Our findings suggest that co-targeting of the MAPK and AR pathways may be effective in patients with an activated MAPK pathway, particularly in patients harboring oncogenic BRAF mutations. These results warrant further investigation of the response to AR inhibitors in BRAF-mutated prostate tumors in clinical settings.

scholarly journals Down-Regulation of AHNAK2 Inhibits Cell Proliferation, Migration and Invasion Through Inactivating the MAPK Pathway in Lung Adenocarcinoma

2020 ◽  
Vol 19 ◽  
pp. 153303382095700
Author(s):  
Dong-Wei Wang ◽  
Hai-Zheng Zheng ◽  
Na Cha ◽  
Xiao-Jie Zhang ◽  
Min Zheng ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Lung Adenocarcinoma ◽  
Mapk Pathway ◽  
A549 Cells ◽  
Mapk Signaling ◽  
Expression Level ◽  
Cell Counting ◽  
Migration And Invasion ◽  
Pcr Analysis

AHNAK nucleoprotein 2 (AHNAK2) has been emerged as a crucial protein for neuroblast differentiation and cell migration, thereby involving in the development of various cancers. However, the specific molecular mechanism of AHNAK2 in lung adenocarcinoma is inconclusive. By accessing to the Oncomine dataset and GEPIA website, a higher expression level of AHNAK2 was observed in lung adenocarcinoma tissue samples. Overall survival (OS) curve plotted by Kaplan-Meier method showed that up-regulation of AHNAK2 was related with poor prognosis of lung adenocarcinoma patients. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis and western blot were conducted to examine the expression level of genes in lung adenocarcinoma cells. Through functional in vitro experiments, cell proliferation, migration and invasion were all suppressed after AHNAK2 knockdown using Cell counting kit-8 (CCK-8) assay, wound-healing and transwell analysis. Reduction of AHNAK2 decreased the apoptosis rate using flow cytometry analysis. Moreover, the key markers of MAPK pathway, p-MEK, p-ERK and p-P90RSK were decreased due to the transfection of si-AHNAK2 in A549 cells. U0126, a MEK inhibitor, showed the similar effects on MAPK-related protein levels with si-AHNAK2. To sum up, AHNAK2 is significantly increased in lung adenocarcinoma and plays a carcinogenic role by activating the MAPK signaling pathway, providing a novel insight and raising possibility for lung adenocarcinoma treatment.

scholarly journals Gancaonin N from Glycyrrhiza uralensis Attenuates the Inflammatory Response by Downregulating the NF-κB/MAPK Pathway on an Acute Pneumonia In Vitro Model

Pharmaceutics ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1028
Author(s):  
Hyun Min Ko ◽  
Seung-Hyeon Lee ◽  
Wona Jee ◽  
Ji Hoon Jung ◽  
Kwan-Il Kim ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Molecular Mechanisms ◽  
Mapk Pathway ◽  
A549 Cells ◽  
Mapk Signaling ◽  
Glycyrrhiza Uralensis ◽  
Raw264.7 Cells ◽  
Acute Pneumonia ◽  
Cox 2 ◽  
Anti Inflammatory

Acute pneumonia is an inflammatory disease caused by several pathogens, with symptoms such as fever and chest pain, to which children are particularly vulnerable. Gancaonin N is a prenylated isoflavone of Glycyrrhiza uralensis that has been used in the treatment of various diseases in oriental medicine. There are little data on the anti-inflammatory efficacy of Gancaonin N, and its effects and mechanisms on acute pneumonia are unknown. Therefore, this study was conducted as a preliminary analysis of the anti-inflammatory effect of Gancaonin N in lipopolysaccharide (LPS)-induced RAW264.7 cells, and to identify its preventive effect on the lung inflammatory response and the molecular mechanisms underlying it. In this study, Gancaonin N inhibited the production of NO and PGE2 in LPS-induced RAW264.7 cells and significantly reduced the expression of iNOS and COX-2 proteins at non-cytotoxic concentrations. In addition, in LPS-induced A549 cells, Gancaonin N significantly reduced the expression of COX-2 and pro-inflammatory cytokines, such as TNF-α, IL-1β, and IL-6. Moreover, Gancaonin N reduced MAPK signaling pathway phosphorylation and NF-κB nuclear translocation. Therefore, Gancaonin N relieved the inflammatory response by inactivating the MAPK and NF-κB signaling pathways; thus, it is a potential natural anti-inflammatory agent that can be used in the treatment of acute pneumonia.

Role of p38 MAPK pathway in apoptosis induction by saturated fatty acid in human pancreatic β-cells

2016 ◽  
Vol 62 (5) ◽  
pp. 13-14
Author(s):  
Jan Šrámek ◽  
Vlasta Němcová-Fürstová ◽  
Kamila Balušíková ◽  
Petr Daniel ◽  
Michael Jelínek ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
P38 Mapk ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Erk Pathway ◽  
Apoptosis Induction ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Pathway Activation

Background. Pancreatic β-cells failure and apoptosis in response to chronically elevated concentrations of saturated fatty acids in blood was considered as one of the main causes of type 2 diabetes mellitus development. Although precise molecular mechanisms of this process are still unclear, there are some indications that the p38 MAPK signaling pathway could be involved.Aim, materials and methods. Therefore, we tested the role of p38 MAPK signaling pathway activation in apoptosis induction by SA in human pancreatic β-cells NES2Y. Crosstalk between p38 MAPK pathway activation and accompanying ERK pathway inhibition after SA application was also tested.Results. We have found that saturated SA at apoptosis-inducing concentration (1 mM) activated the p38 MAPK signaling pathway MKK3/6→p38 MAPK→MAPKAPK-2 and inhibited the ERK signaling pathway c-Raf→MEK1/2→ERK1/2. The inhibition of p38 MAPK expression by siRNA silencing had no significant effect on cell viability or the level of phosphorylated ERK pathway members after SA administration. The inhibition of p38 MAPK activity by the specific inhibitor SB202190 resulted in noticeable activation of ERK pathway members after SA treatment but in no significant effect on cell viability. p38 MAPK overexpression by plasmid transfection produced no significant influence on cell viability or ERK pathway activation after SA exposure. The activation of p38 MAPK by the specific activator anisomycin led to apoptosis induction similar to application of SA (PARP cleavage and caspase-7, -8, and -9 activation) and in inhibition of ERK pathway members.Conclusions. We demonstrated that apoptosis-inducing concentrations of SA activate the p38 MAPK signaling pathway and that this activation could be involved in apoptosis induction by SA in the human pancreatic β-cells NES2Y. However, this involvement does not seem to play a key role. Crosstalk between p38 MAPK pathway activation and ERK pathway inhibition in NES2Y cells seems likely. Thus, the ERK pathway inhibition by p38 MAPK activation does not also seem to be essential for SA-induced apoptosis.

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