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Involvement of the MAPK Pathway in Cancer and Immunology

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 9111

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Dr. Gatien Moriceau

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Guest Editor

Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
Interests: MAPK pathway; melanoma; drug resistance; immunology

Special Issue Information

Dear Colleagues,

The Mitogen-Activated Protein Kinase (MAPK) pathway and its associated mutations are known to be involved in tumorigenesis, and the development of small-molecule inhibitors targeting the different players of this pathway has been proposed as a potential new therapeutic, resulting in prolonged patient survival. The understanding of how these mutations molecularly impact the MAPK pathway regulation and its protein–protein interactions is the next step towards more defined drug development. Another important area of interest is the relationship between the MAPK pathway, its small-molecule inhibitors and the different compartments of the immune system in the context of the tumor micro environment (TME). A durably effective MAPK-inhibitor-based therapy could prevent MAPK resistance (reactivation) and preserve and/or promote antitumor T-cell immunity.

This Special Issue is focused on the MAPK pathway, and welcome original articles and reviews on aspects related to the molecular and pharmacological mechanisms of drugs targeting the MAPK pathway in cancers. Potential topics include, but are not limited to, drug development, protein–protein interactions, and the impact of MAPK inhibitors on the immune system.

Dr. Gatien Moriceau
Guest Editor

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Keywords

melanoma
colon cancer
MAPK pathway
mutations
drug development
drug resistance
immunotherapy and MAPK

Published Papers (5 papers)

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Research

17 pages, 3584 KiB

Open AccessArticle

Regulation of Cortico-Thalamic JNK1/2 and ERK1/2 MAPKs and Apoptosis-Related Signaling Pathways in PDYN Gene-Deficient Mice Following Acute and Chronic Mild Stress

by Fernando Yáñez-Gómez, Alfredo Ramos-Miguel, Jesús A. García-Sevilla, Jorge Manzanares and Teresa Femenía

Int. J. Mol. Sci. 2023, 24(3), 2303; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24032303 - 24 Jan 2023

Viewed by 1537

Abstract

The crosstalk between the opioidergic system and mitogen-activated protein kinases (MAPKs) has a critical role in mediating stress-induced behaviors related to the pathophysiology of anxiety. The present study evaluated the basal status and stress-induced alterations of cortico-thalamic MAPKs and other cell fate-related signaling pathways potentially underlying the anxiogenic endophenotype of PDYN gene-deficient mice. Compared to littermates, PDYN knockout (KO) mice had lower cortical and or thalamic amounts of the phospho-activated MAPKs c-Jun N-terminal kinase (JNK1/2) and extracellular signal-regulated kinase (ERK1/2). Similarly, PDYN-KO animals displayed reduced cortico-thalamic densities of total and phosphorylated (at Ser191) species of the cell fate regulator Fas-associated protein with death domain (FADD) without alterations in the Fas receptor. Exposure to acute restraint and chronic mild stress stimuli induced the robust stimulation of JNK1/2 and ERK1/2 MAPKs, FADD, and Akt-mTOR pathways, without apparent increases in apoptotic rates. Interestingly, PDYN deficiency prevented stress-induced JNK1/2 and FADD but not ERK1/2 or Akt-mTOR hyperactivations. These findings suggest that cortico-thalamic MAPK- and FADD-dependent neuroplasticity might be altered in PDYN-KO mice. In addition, the results also indicate that the PDYN gene (and hence dynorphin release) may be required to stimulate JNK1/2 and FADD (but not ERK1/2 or Akt/mTOR) pathways under environmental stress conditions. Full article

(This article belongs to the Special Issue Involvement of the MAPK Pathway in Cancer and Immunology)

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18 pages, 2213 KiB

Open AccessArticle

Optimized Transcriptional Signature for Evaluation of MEK/ERK Pathway Baseline Activity and Long-Term Modulations in Ovarian Cancer

by Mikhail S. Chesnokov, Anil Yadav and Ilana Chefetz

Int. J. Mol. Sci. 2022, 23(21), 13365; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232113365 - 01 Nov 2022

Cited by 1 | Viewed by 1830

Abstract

Ovarian cancer is the most aggressive and lethal of all gynecologic malignancies. The high activity of the MEK/ERK signaling pathway is tightly associated with tumor growth, high recurrence rate, and treatment resistance. Several transcriptional signatures were proposed recently for evaluation of MEK/ERK activity in tumor tissue. In the present study, we validated the performance of a robust multi-cancer MPAS 10-gene signature in various experimental models and publicly available sets of ovarian cancer samples. Expression of four MPAS genes (PHLDA1, DUSP4, EPHA2, and SPRY4) displayed reproducible responses to MEK/ERK activity modulations across several experimental models in vitro and in vivo. Levels of PHLDA1, DUSP4, and EPHA2 expression were also significantly associated with baseline levels of MEK/ERK pathway activity in multiple human ovarian cancer cell lines and ovarian cancer patient samples available from the TCGA database. Initial platinum therapy resistance and advanced age at diagnosis were independently associated with poor overall patient survival. Taken together, our results demonstrate that the performance of transcriptional signatures is significantly affected by tissue specificity and aspects of particular experimental models. We therefore propose that gene expression signatures derived from comprehensive multi-cancer studies should be always validated for each cancer type. Full article

(This article belongs to the Special Issue Involvement of the MAPK Pathway in Cancer and Immunology)

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14 pages, 2631 KiB

Open AccessArticle

Shuterin Enhances the Cytotoxicity of the Natural Killer Leukemia Cell Line KHYG-1 by Increasing the Expression Levels of Granzyme B and IFN-γ through the MAPK and Ras/Raf Signaling Pathways

by Jen-Tsun Lin, Yi-Ching Chuang, Mu-Kuan Chen, Yu-Sheng Lo, Chia-Chieh Lin, Hsin-Yu Ho, Yen-Tze Liu and Ming-Ju Hsieh

Int. J. Mol. Sci. 2022, 23(21), 12816; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232112816 - 24 Oct 2022

Cited by 2 | Viewed by 1545

Abstract

Natural killer (NK) cell therapy is an emerging tool for cancer immunotherapy. NK cells are isolated from peripheral blood, and their number and activity are limited. Therefore, primary NK cells should be expanded substantially, and their proliferation and cytotoxicity must be enhanced. Shuterin is a phytochemical isolated from Ficus thonningii. In this study, we explored the possible capacity of shuterin to enhance the proliferation and activity of KHYG-1 cells (an NK leukemia cell line). Shuterin enhanced the proliferation of KHYG-1 cells and their cytotoxicity to K562 cells. Moreover, this phytochemical induced the expression of granzyme B by promoting the phosphorylated cyclic adenosine monophosphate response element–binding protein (CREB) and mitogen-activated protein kinase (MAPK) signaling pathways. Furthermore, the secretion of interferon (IFN)-γ increased with increasing levels of shuterin in KHYG-1 cells and NK cells obtained from adults with head and neck squamous cell carcinoma. Shuterin appeared to induce IFN-γ secretion by increasing the expression of lectin-like transcript 1 and the phosphorylation of proteins involved in the Ras/Raf pathway. Thus, shuterin represents a promising agent for promoting the proliferation and cytotoxicity of NK cells. Full article

(This article belongs to the Special Issue Involvement of the MAPK Pathway in Cancer and Immunology)

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19 pages, 5435 KiB

Open AccessArticle

Metal Ion Periplasmic-Binding Protein YfeA of Glaesserella parasuis Induces the Secretion of Pro-Inflammatory Cytokines of Macrophages via MAPK and NF-κB Signaling through TLR2 and TLR4

by Zhen Yang, Xinwei Tang, Kang Wang, Ke Dai, Yung-Fu Chang, Senyan Du, Qin Zhao, Xiaobo Huang, Rui Wu, Qigui Yan, Sanjie Cao and Yiping Wen

Int. J. Mol. Sci. 2022, 23(17), 9627; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23179627 - 25 Aug 2022

Cited by 3 | Viewed by 1663

Abstract

The YfeA gene, belonging to the well-conserved ABC (ATP-binding cassette) transport system Yfe, encodes the substrate-binding subunit of the iron, zinc, and manganese transport system in bacteria. As a potential vaccine candidate in Glaesserella parasuis, the functional mechanisms of YfeA in the infection process remain obscure. In this study, vaccination with YfeA effectively protected the C56BL6 mouse against the G. parasuis SC1401 challenge. Bioinformatics analysis suggests that YfeA is highly conserved in G. parasuis, and its metal-binding sites have been strictly conserved throughout evolution. Stimulation of RAW 264.7 macrophages with YfeA verified that toll-like receptors (TLR) 2 and 4 participated in the positive transcription and expression of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α. The activation of TLR2 and TLR4 utilized the MyD88/MAL and TRIF/TRAM pairs to initiate TLRs signaling. Furthermore, YfeA was shown to stimulate nuclear translocation of NF-κB and activated diverse mitogen-activated protein (MAP) kinase signaling cascades, which are specific to the secretion of particular cytokine(s) in murine macrophages. Separate blocking TLR2, TLR4, MAPK, and RelA (p65) pathways significantly decreased YfeA-induced pro-inflammatory cytokine production. In addition, YfeA-stimulated RAW 264.7 produces the pro-inflammatory hallmark, reactive oxygen species (ROS). In conclusion, our findings indicate that YfeA is a novel pro-inflammatory mediator in G. parasuis and induces TLR2 and TLR4-dependent pro-inflammatory activity in RAW 264.7 macrophages through P38, JNK-MAPK, and NF-κB signaling pathways. Full article

(This article belongs to the Special Issue Involvement of the MAPK Pathway in Cancer and Immunology)

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14 pages, 4833 KiB

Open AccessArticle

Ciliary Neurotrophic Factor (CNTF) Inhibits In Vitro Cementoblast Mineralization and Induces Autophagy, in Part by STAT3/ERK Commitment

by Jiawen Yong, Sabine Gröger, Julia von Bremen and Sabine Ruf

Int. J. Mol. Sci. 2022, 23(16), 9311; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23169311 - 18 Aug 2022

Cited by 3 | Viewed by 1877

Abstract

In animal models, the administration of ciliary neurotrophic factor (CNTF) was demonstrated to reduce bone mass and to participate in bone remodeling. Cementoblasts, a cell type embedded in the cementum, are the main cells to produce and mineralize the extracellular matrix. The effect of CNTF on cementoblasts has not yet been addressed. Thus, the goal of this in vitro study was to investigate possible influences of exogenous CNTF on cementogenesis, as well as autophagy regulation and subsequent mechanisms in cementoblasts. Cementoblasts (OCCM-30) were stimulated with exogenous CNTF. Alizarin Red staining was performed to analyze the functional differentiation (mineralization) of OCCM-30 cells. The release of OPG was quantified by ELISA. The expression of cementogenesis markers (RUNX-2, OCN, BMP-7, BSP, and SPON-2) was evaluated by RT-qPCR. Western blotting (WB) was performed for the protein expression of STAT3, COX-2, SHP-2, cPLAα, cPLAβ; ERK1/2, P38, and JNK. The autophagic flux was assessed using WB and RT-qPCR analysis of LC3A/B, Beclin-1, and Atg-5, and the autophagosome was investigated by immunofluorescence staining (IF). The ERK1/2 (FR180204) or STAT3 (sc-202818) antagonist was added, and the cellular response was analyzed using flow cytometry. Exogenous CNTF significantly attenuated mineralized nodule formation, impaired OPG release, and downregulated the mRNA levels of RUNX-2, OCN, BMP-7, and BSP. Moreover, CNTF induced the phosphorylation of STAT3 and activated a transient activation of SHP-2, cPLAβ, ERK1/2, P38, and JNK protein. CNTF also induced autophagosome formation and promoted autophagy-associated gene and protein expressions. Additionally, the inhibition of ERK1/2 or STAT3 reversed a CNTF-induced mineralization impairment and had regulatory effects on CNTF-induced autophagosome formation. Our data revealed that CNTF acts as a potent inhibitor of cementogenesis, and it can trigger autophagy, in part by ERK1/2 and STAT3 commitment in the cementoblasts. Thus, it may play an important role in inducing or facilitating inflammatory root resorption during orthodontic tooth movement. Full article

(This article belongs to the Special Issue Involvement of the MAPK Pathway in Cancer and Immunology)

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