scholarly journals p38β and Cancer: The Beginning of the Road

2020 ◽  
Vol 21 (20) ◽  
pp. 7524
Author(s):  
Olga Roche ◽  
Diego M. Fernández-Aroca ◽  
Elena Arconada-Luque ◽  
Natalia García-Flores ◽  
Liliana F. Mellor ◽  
...  
Keyword(s):  
Therapeutic Target ◽  
Cancer Biology ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
The Road ◽  
Different Types ◽  
Mitogen Activated Protein ◽  
P38mapk Signaling ◽  
Important Therapeutic Target

The p38 mitogen-activated protein kinase (MAPK) signaling pathway is implicated in cancer biology and has been widely studied over the past two decades as a potential therapeutic target. Most of the biological and pathological implications of p38MAPK signaling are often associated with p38α (MAPK14). Recently, several members of the p38 family, including p38γ and p38δ, have been shown to play a crucial role in several pathologies including cancer. However, the specific role of p38β (MAPK11) in cancer is still elusive, and further investigation is needed. Here, we summarize what is currently known about the role of p38β in different types of tumors and its putative implication in cancer therapy. All evidence suggests that p38β might be a key player in cancer development, and could be an important therapeutic target in several pathologies, including cancer.

scholarly journals Targeting MAPK Signaling in Cancer: Mechanisms of Drug Resistance and Sensitivity

2020 ◽  
Vol 21 (3) ◽  
pp. 1102 ◽  
Author(s):  
Shannon Lee ◽  
Jens Rauch ◽  
Walter Kolch
Keyword(s):  
Drug Sensitivity ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Signal Transduction Pathways ◽  
Erk Pathway ◽  
Mapk Pathways ◽  
Extracellular Signaling ◽  
New Findings ◽  
Mitogen Activated Protein

Mitogen-activated protein kinase (MAPK) pathways represent ubiquitous signal transduction pathways that regulate all aspects of life and are frequently altered in disease. Here, we focus on the role of MAPK pathways in modulating drug sensitivity and resistance in cancer. We briefly discuss new findings in the extracellular signaling-regulated kinase (ERK) pathway, but mainly focus on the mechanisms how stress activated MAPK pathways, such as p38 MAPK and the Jun N-terminal kinases (JNK), impact the response of cancer cells to chemotherapies and targeted therapies. In this context, we also discuss the role of metabolic and epigenetic aberrations and new therapeutic opportunities arising from these changes.

scholarly journals Autophagy as a therapeutic target in pancreatic cancer

2020 ◽  
Author(s):  
Max Piffoux ◽  
Erwan Eriau ◽  
Philippe A. Cassier
Keyword(s):  
Targeted Therapy ◽  
Therapeutic Target ◽  
Molecular Mechanisms ◽  
Mitogen Activated Protein Kinase ◽  
Ductal Adenocarcinoma ◽  
Extracellular Signal ◽  
Anti Cancer ◽  
Mitogen Activated Protein ◽  
Cellular Components

Abstract Pancreatic ductal adenocarcinoma (PDAC) is characterised by early metastasis and resistance to anti-cancer therapy, leading to an overall poor prognosis. Despite continued research efforts, no targeted therapy has yet shown meaningful efficacy in PDAC; mutations in the oncogene KRAS and the tumour suppressor TP53, which are the most common genomic alterations in PDAC, have so far shown poor clinical actionability. Autophagy, a conserved process allowing cells to recycle altered or unused organelles and cellular components, has been shown to be upregulated in PDAC and is implicated in resistance to both cytotoxic chemotherapy and targeted therapy. Autophagy is thus regarded as a potential therapeutic target in PDAC and other cancers. Although the molecular mechanisms of autophagy activation in PDAC are only beginning to emerge, several groups have reported interesting results when combining inhibitors of the extracellular-signal-regulated kinase/mitogen-activated protein kinase pathway and inhibitors of autophagy in models of PDAC and other KRAS-driven cancers. In this article, we review the existing preclinical data regarding the role of autophagy in PDAC, as well as results of relevant clinical trials with agents that modulate autophagy in this cancer.

scholarly journals Role of Muramyl Dipeptide in Lipopolysaccharide-Mediated Biological Activity and Osteoclast Activity

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Hideki Kitaura ◽  
Masahiko Ishida ◽  
Keisuke Kimura ◽  
Haruki Sugisawa ◽  
Akiko Kishikawa ◽  
...  
Keyword(s):  
Biological Activities ◽  
Muramyl Dipeptide ◽  
Mapk Signaling ◽  
Osteoclast Formation ◽  
Mitogen Activated Protein Kinase ◽  
Immunological Activity ◽  
Mitogen Activated Protein

Lipopolysaccharide (LPS) is an endotoxin and bacterial cell wall component that is capable of inducing inflammation and immunological activity. Muramyl dipeptide (MDP), the minimal essential structural unit responsible for the immunological activity of peptidoglycans, is another inflammation-inducing molecule that is ubiquitously expressed by bacteria. Several studies have shown that inflammation-related biological activities were synergistically induced by interactions between LPS and MDP. MDP synergistically enhances production of proinflammatory cytokines that are induced by LPS exposure. Injection of MDP induces lethal shock in mice challenged with LPS. LPS also induces osteoclast formation and pathological bone resorption; MDP enhances LPS induction of both processes. Furthermore, MDP enhances the LPS-induced receptor activator of NF-κB ligand (RANKL) expression and toll-like receptor 4 (TLR4) expression bothin vivoandin vitro. Additionally, MDP enhances LPS-induced mitogen-activated protein kinase (MAPK) signaling in stromal cells. Taken together, these findings suggest that MDP plays an important role in LPS-induced biological activities. This review discusses the role of MDP in LPS-mediated biological activities, primarily in relation to osteoclastogenesis.

scholarly journals Bark tissue transcriptome analyses of inverted Populus yunnanensis cuttings reveal the crucial role of plant hormones in response to inversion

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e7740 ◽  
Author(s):  
An-Pei Zhou ◽  
Pei-Hua Gan ◽  
Dan Zong ◽  
Xuan Fei ◽  
Yuan-Yuan Zhong ◽  
...  
Keyword(s):  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Receptor Kinase ◽  
Ethylene Response ◽  
Mitogen Activated Protein ◽  
Bark Tissue ◽  
Plant Pathogen Interaction ◽  
Transcriptomic Changes ◽  
Stem Position

Inverted cuttings of Populus yunnanensis exhibit an interesting growth response to inversion. This response is characterized by enlargement of the stem above the shoot site, while the upright stem shows obvious outward growth below the shoot site. In this study, we examined transcriptome changes in bark tissue at four positions on upright and inverted cuttings of P. yunnanensis: position B, the upper portion of the stem; position C, the lower portion of the stem; position D, the bottom of new growth; and position E, the top of new growth. The results revealed major transcriptomic changes in the stem, especially at position B, but little alteration was observed in the bark tissue of the new shoot. The differentially expressed genes (DEGs) were mainly assigned to four pathways: plant hormone signal transduction, plant-pathogen interaction, mitogen-activated protein kinase (MAPK) signaling pathway-plant, and adenosine triphosphate-binding cassette (ABC) transporters. Most of these DEGs were involved in at least two pathways. The levels of many hormones, such as auxin (IAA), cytokinin (CTK), gibberellins (GAs), ethylene (ET), and brassinosteroids (BRs), underwent large changes in the inverted cuttings. A coexpression network showed that the top 20 hub unigenes at position B in the upright and inverted cutting groups were associated mainly with the BR and ET signaling pathways, respectively. Furthermore, brassinosteroid insensitive 1-associated receptor kinase 1 (BAK1) in the BR pathway and both ethylene response (ETR) and constitutive triple response 1 (CTR1) in the ET pathway were important hubs that interfaced with multiple pathways.

scholarly journals Results of TETimaX Trial of Langerhans Cell Histiocytosis Treatment and Perspectives on the Role of Imatinib Mesylate in the Era of MAPK Signaling

Biomedicines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1759
Author(s):  
Liliana Montella ◽  
Margaret Ottaviano ◽  
Vittorio Riccio ◽  
Fernanda Picozzi ◽  
Gaetano Facchini ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Langerhans Cell Histiocytosis ◽  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Mapk Signaling ◽  
Langerhans Cell ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein

Langerhans cell histiocytosis (LCH) is a rare disease that has a variable clinical presentation and unpredictable behavior. Until recently, therapeutic options were limited. Insights into the role of mitogen-activated protein kinase (MAPK) signaling have allowed the increased use of targeted treatments. Before the advent of drugs that interfere with this pathway, investigations concerning the tyrosine kinase inhibitor imatinib opened the way to a rationale-based therapeutic approach to the disease. Imatinib block the binding site of ATP in the BCR/ABL protein and is also a platelet-derived growth factor receptor (PDGFR) and a KIT (CD117) kinase inhibitor. A case of refractory LCH with brain involvement was reported to be successfully treated with imatinib. Thereafter, we further explored the role of this tyrosine kinase inhibitor. The present study is composed of an immunohistochemical evaluation of PDGFRβ expression and a clinical evaluation of imatinib in a series of LCH patients. In the first part, a series of 10 samples obtained from LCH patients was examined and a strong immunohistochemistry expression of PDGFRβ was found in 40% of the cases. In the clinical part of the study, five patients were enrolled. Long-lasting disease control was obtained. These results may suggest a potential role for this drug in the current age.

scholarly journals Adenosine Triphosphate Activates Mitogen-Activated Protein Kinase in Human Granulosa-Luteal Cells*

Endocrinology ◽  
2001 ◽  
Vol 142 (4) ◽  
pp. 1554-1560 ◽  
Author(s):  
Chen-Jei Tai ◽  
Sung Keun Kang ◽  
Chii-Ruey Tzeng ◽  
Peter C. K. Leung
Keyword(s):  
Protein Kinase ◽  
Signaling Pathway ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Intracellular Camp ◽  
Human Ovary ◽  
Luteal Cells ◽  
Mitogen Activated Protein

Abstract ATP has been shown to activate the phospholipase C/diacylglycerol/protein kinase C (PKC) pathway. However, little is known about the downstream signaling events. The present study was designed to examine the effect of ATP on activation of the mitogen-activated protein kinase (MAPK) signaling pathway and its physiological role in human granulosa-luteal cells. Western blot analysis, using a monoclonal antibody that detected the phosphorylated forms of extracellular signal-regulated kinase-1 and -2 (p42mapk and p44 mapk, respectively), demonstrated that ATP activated MAPK in a dose- and time-dependent manner. Treatment of the cells with suramin (a P2 purinoceptor antagonist), neomycin (a phospholipase C inhibitor), staurosporin (a PKC inhibitor), or PD98059 (an MAPK/ERK kinase inhibitor) significantly attenuated the ATP-induced activation of MAPK. In contrast, ATP-induced MAPK activation was not significantly affected by pertussis toxin (a Gi inhibitor). To examine the role of Gs protein, the intracellular cAMP level was determined after treatment with ATP or hCG. No significant elevation of intracellular cAMP was noted after ATP treatment. To determine the role of MAPK in steroidogenesis, human granulosa-luteal cells were treated with ATP, hCG, or ATP plus hCG in the presence or absence of PD98059. RIA revealed that ATP alone did not significantly affect the basal progesterone concentration. However, hCG-induced progesterone production was reduced by ATP treatment. PD98059 reversed the inhibitory effect of ATP on hCG-induced progesterone production. To our knowledge, this is the first demonstration of ATP-induced activation of the MAPK signaling pathway in the human ovary. These results support the idea that the MAPK signaling pathway is involved in mediating ATP actions in the human ovary.

CypA: a Potential Target of Tumor Radiotherapy and/or Chemotherapy

2020 ◽  
Vol 27 ◽  
Author(s):  
Man-Yu Chu ◽  
He-Cheng Huang ◽  
En-Ming Li ◽  
Li-Yan Xu
Keyword(s):  
Cancer Chemotherapy ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Cycle Arrest ◽  
Mitogen Activated Protein ◽  
Intracellular Target ◽  
Related Proteins ◽  
The Impact ◽  
Mapk Signaling Pathways

: Cyclophilin A (CypA) is a ubiquitous and highly conserved protein. CypA, the intracellular target protein for the immunosuppressant cyclosporine A (CsA), plays important cellular roles through peptidyl-prolyl cis-trans isomerase (PPIase). Increasing evidence shows that CypA is up-regulated in a variety of human cancers. In addition to being involved in the occurrence and development of multiple tumors, overexpression of CypA also has been shown to be strongly associated with malignant transformation. Surgery, chemotherapy and radiotherapy are the three main treatments for cancer. Chemotherapy and radiotherapy are often used as direct or adjuvant treatments for cancer. However, various side effects and resistance to both chemotherapy and radiotherapy bring great challenges to these two forms of treatment. According recent reports, CypA can improve the chemosensitivity and/or radiosensitivity of cancers, possibly by affecting the expression of drug-resistant related proteins, cell cycle arrest and activation of the mitogen-activated protein kinase (MAPK) signaling pathways. In this review, we focus on the role of CypA in cancer, the impact on cancer chemotherapeutic and radiotherapy sensitivity, and the mechanism of action. It is suggested that CypA may be a novel potential therapeutic target for cancer chemotherapy and/or radiotherapy.

scholarly journals The Ebola virus soluble glycoprotein contributes to viral pathogenesis by activating the MAP kinase signaling pathway

2021 ◽  
Vol 17 (9) ◽  
pp. e1009937
Author(s):  
Wakako Furuyama ◽  
Kyle Shifflett ◽  
Heinz Feldmann ◽  
Andrea Marzi
Keyword(s):  
Signaling Pathway ◽  
Ebola Virus ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Hek293 Cells ◽  
Huh7 Cells ◽  
Mitogen Activated Protein

Ebola virus (EBOV) expresses three different glycoproteins (GPs) from its GP gene. The primary product, soluble GP (sGP), is secreted in abundance during infection. EBOV sGP has been discussed as a potential pathogenicity factor, however, little is known regarding its functional role. Here, we analyzed the role of sGP in vitro and in vivo. We show that EBOV sGP has two different functions that contribute to infectivity in tissue culture. EBOV sGP increases the uptake of virus particles into late endosomes in HEK293 cells, and it activates the mitogen-activated protein kinase (MAPK) signaling pathway leading to increased viral replication in Huh7 cells. Furthermore, we analyzed the role of EBOV sGP on pathogenicity using a well-established mouse model. We found an sGP-dependent significant titer increase of EBOV in the liver of infected animals. These results provide new mechanistic insights into EBOV pathogenicity and highlight EBOV sGP as a possible therapeutic target.

The Role of MAPK's Signaling in Mediating ApoE4-Driven Pathology In Vivo

2019 ◽  
Vol 16 (4) ◽  
pp. 281-292 ◽  
Author(s):  
Shiran Salomon-Zimri ◽  
Amit Koren ◽  
Ariel Angel ◽  
Tali Ben-Zur ◽  
Daniel Offen ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Adeno Associated Virus ◽  
Immunoblot Assay ◽  
Total Level ◽  
Mitogen Activated Protein

Background: Alzheimer's Disease (AD) is associated with impairments in key brain Mitogen- Activated Protein Kinase (MAPK) signaling cascades including the p38, c-Jun N-terminal kinase (JNK), ERK and Akt pathways. Apolipoprotein E4 (ApoE4) is the most prevalent genetic risk factor of AD. Objectives: To investigate the extent to which the MAPK signaling pathway plays a role in mediating the pathological effects of apoE4 and can be reversed by experimental manipulations. Methods: Measurements of total level and activation of MAPK signaling pathway factors, obtained utilizing immunoblot assay of hippocampal tissues from naïve and viral-treated apoE3 and apoE4 targeted replacement mice. Methods: Measurements of total level and activation of MAPK signaling pathway factors, obtained utilizing immunoblot assay of hippocampal tissues from naïve and viral-treated apoE3 and apoE4 targeted replacement mice. Results: ApoE4 mice showed robust activation of the stress related p38 and JNK pathways and a corresponding decrease in Akt activity, which is coupled to activation of GSK3β and tau hyperphosphorylation. There was no effect on the ERK pathway. We have previously shown that the apoE4- related pathology, namely; accumulation of Aβ, hyper-phosphorylated tau, synaptic impairments and decreased VEGF levels can be reversed by up-regulation of VEGF level utilizing a VEGF-expressing adeno-associated virus. Utilizing this approach, we assessed the extent to which the AD-hallmark and synaptic pathologies of apoE4 are related to the corresponding MAPK signaling effects. This revealed that the reversal of the apoE4-driven pathology via VEGF treatment was associated with a reversal of the p38 and Akt related effects. Conclusion: Taken together, these results suggest that the p38 and Akt pathways play a role in mediating the AD-related pathological effects of apoE4 in the hippocampus.

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