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Special Issue "Targeting MAPK in Cancer 2.0"

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

Deadline for manuscript submissions: closed (30 September 2021).

Special Issue Editor

Dr. Elisabetta Rovida
E-Mail Website
Guest Editor
Dipartimento di Scienze Biomediche, Sperimentali e Cliniche, University of Florence, Florence, Italy
Interests: MAPK; protein phosphorylation; cancer; ERK5; targeted therapy; resistance mechanisms; CSF1/CSF1R; RTK
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is a continuation of our previous Special Issue “Targeting MAPK in Cancer”.

Mitogen-activated protein kinase (MAPK) pathways are prominently involved in the onset and progression of cancer. Aberrant activation of MAPK pathways mostly affects Ras and B-Raf in the extracellular signal-regulated kinase 1/2 pathway. On the other hand, the relevance of Jun N-terminal kinase and p38 in cancer is less known, although these pathways seem to predominantly counteract, rather that to support, the malignant phenotype. Interestingly, ERK5 is emerging as an additional possible target for cancer therapy, while the possibility to exploit ERK7/ERK8-targeted therapy still lacks a rationale. In this Special Issue, we aim to highlight the contribution of all MAPK in cancer biology and to outline how to target these pathways in order to effectively reduce cancer growth and spreading.

As Guest Editor of the International Journal of Molecular Sciences (https://0-www-mdpi-com.brum.beds.ac.uk/journal/ijms), I am pleased to announce the opening for submission to a Special Issue entitled “Targeting MAPK in Cancer”. This Special Issue is open to both original research articles and review articles.

I look forward to your response regarding your contribution to this Special Issue.

Dr. Elisabetta Rovida
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • MAPK
  • targeted therapy
  • resistance mechanisms
  • p38
  • cancer
  • JNK
  • ERK5/MAPK7
  • ERK8/MAPK15
  • ERK1/2
  • MEK
  • MEKK

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Published Papers (14 papers)

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Research

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Article
The Hedgehog-GLI Pathway Regulates MEK5-ERK5 Expression and Activation in Melanoma Cells
Int. J. Mol. Sci. 2021, 22(20), 11259; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222011259 - 19 Oct 2021
Viewed by 244
Abstract
Malignant melanoma is the deadliest skin cancer, with a poor prognosis in advanced stages. We recently showed that the extracellular signal-regulated kinase 5 (ERK5), encoded by the MAPK7 gene, plays a pivotal role in melanoma by regulating cell functions necessary for tumour development, [...] Read more.
Malignant melanoma is the deadliest skin cancer, with a poor prognosis in advanced stages. We recently showed that the extracellular signal-regulated kinase 5 (ERK5), encoded by the MAPK7 gene, plays a pivotal role in melanoma by regulating cell functions necessary for tumour development, such as proliferation. Hedgehog-GLI signalling is constitutively active in melanoma and is required for proliferation. However, no data are available in literature about a possible interplay between Hedgehog-GLI and ERK5 pathways. Here, we show that hyperactivation of the Hedgehog-GLI pathway by genetic inhibition of the negative regulator Patched 1 increases the amount of ERK5 mRNA and protein. Chromatin immunoprecipitation showed that GLI1, the major downstream effector of Hedgehog-GLI signalling, binds to a functional non-canonical GLI consensus sequence at the MAPK7 promoter. Furthermore, we found that ERK5 is required for Hedgehog-GLI-dependent melanoma cell proliferation, and that the combination of GLI and ERK5 inhibitors is more effective than single treatments in reducing cell viability and colony formation ability in melanoma cells. Together, these findings led to the identification of a novel Hedgehog-GLI-ERK5 axis that regulates melanoma cell growth, and shed light on new functions of ERK5, paving the way for new therapeutic options in melanoma and other neoplasms with active Hedgehog-GLI and ERK5 pathways. Full article
(This article belongs to the Special Issue Targeting MAPK in Cancer 2.0)
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Article
Iron Chelator Induces Apoptosis in Osteosarcoma Cells by Disrupting Intracellular Iron Homeostasis and Activating the MAPK Pathway
Int. J. Mol. Sci. 2021, 22(13), 7168; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22137168 - 02 Jul 2021
Cited by 1 | Viewed by 713
Abstract
Osteosarcoma is a common malignant bone tumor in clinical orthopedics. Iron chelators have inhibitory effects on many cancers, but their effects and mechanisms in osteosarcoma are still uncertain. Our in vitro results show that deferoxamine (DFO) and deferasirox (DFX), two iron chelators, significantly [...] Read more.
Osteosarcoma is a common malignant bone tumor in clinical orthopedics. Iron chelators have inhibitory effects on many cancers, but their effects and mechanisms in osteosarcoma are still uncertain. Our in vitro results show that deferoxamine (DFO) and deferasirox (DFX), two iron chelators, significantly inhibited the proliferation of osteosarcoma cells (MG-63, MNNG/HOS and K7M2). The viability of osteosarcoma cells was decreased by DFO and DFX in a concentration-dependent manner. DFO and DFX generated reactive oxygen species (ROS), altered iron metabolism and triggered apoptosis in osteosarcoma cells. Iron chelator-induced apoptosis was due to the activation of the MAPK signaling pathway, with increased phosphorylation levels of JNK, p38 and ERK, and ROS generation; in this process, the expression of C-caspase-3 and C-PARP increased. In an orthotopic osteosarcoma transplantation model, iron chelators (20 mg/kg every day, Ip, for 14 days) significantly inhibited the growth of the tumor. Immunohistochemical analysis showed that iron metabolism was altered, apoptosis was promoted, and malignant proliferation was reduced with iron chelators in the tumor tissues. In conclusion, we observed that iron chelators induced apoptosis in osteosarcoma by activating the ROS-related MAPK signaling pathway. Because iron is crucial for cell proliferation, iron chelators may provide a novel therapeutic strategy for osteosarcoma. Full article
(This article belongs to the Special Issue Targeting MAPK in Cancer 2.0)
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Article
Horizontal Combination of MEK and PI3K/mTOR Inhibition in BRAF Mutant Tumor Cells with or without Concomitant PI3K Pathway Mutations
Int. J. Mol. Sci. 2020, 21(20), 7649; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207649 - 16 Oct 2020
Viewed by 678
Abstract
The RAS/RAF and PI3K/Akt pathways play a key regulatory role in cancer and are often hit by oncogenic mutations. Despite molecular targeting, the long-term success of monotherapy is often hampered by de novo or acquired resistance. In the case of concurrent mutations in [...] Read more.
The RAS/RAF and PI3K/Akt pathways play a key regulatory role in cancer and are often hit by oncogenic mutations. Despite molecular targeting, the long-term success of monotherapy is often hampered by de novo or acquired resistance. In the case of concurrent mutations in both pathways, horizontal combination could be a reasonable approach. In our study, we investigated the MEK inhibitor selumetinib and PI3K/mTOR dual inhibitor BEZ235 alone and in combination in BRAF-only mutant and BRAF + PI3K/PTEN double mutant cancer cells using short- and long-term 2D viability assays, spheroid assays, and immunoblots. In the 2D assays, selumetinib was more effective on BRAF-only mutant lines when compared to BRAF + PI3K/PTEN double mutants. Furthermore, combination therapy had an additive effect in most of the lines while synergism was observed in two of the double mutants. Importantly, in the SW1417 BRAF + PI3K double mutant cells, synergism was also confirmed in the spheroid and in the in vivo model. Mechanistically, p-Akt level decreased only in the SW1417 cell line after combination treatment. In conclusion, the presence of concurrent mutations alone did not predict a stronger response to combination treatment. Therefore, additional investigations are warranted to identify predictive factors that can select patients who can benefit from the horizontal combinational inhibition of these two pathways. Full article
(This article belongs to the Special Issue Targeting MAPK in Cancer)
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Article
SUMOylation Is Required for ERK5 Nuclear Translocation and ERK5-Mediated Cancer Cell Proliferation
Int. J. Mol. Sci. 2020, 21(6), 2203; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21062203 - 23 Mar 2020
Cited by 7 | Viewed by 1525
Abstract
The MAP kinase ERK5 contains an N-terminal kinase domain and a unique C-terminal tail including a nuclear localization signal and a transcriptional activation domain. ERK5 is activated in response to growth factors and stresses and regulates transcription at the nucleus by either phosphorylation [...] Read more.
The MAP kinase ERK5 contains an N-terminal kinase domain and a unique C-terminal tail including a nuclear localization signal and a transcriptional activation domain. ERK5 is activated in response to growth factors and stresses and regulates transcription at the nucleus by either phosphorylation or interaction with transcription factors. MEK5-ERK5 pathway plays an important role regulating cancer cell proliferation and survival. Therefore, it is important to define the precise molecular mechanisms implicated in ERK5 nucleo-cytoplasmic shuttling. We previously described that the molecular chaperone Hsp90 stabilizes and anchors ERK5 at the cytosol and that ERK5 nuclear shuttling requires Hsp90 dissociation. Here, we show that MEK5 or overexpression of Cdc37—mechanisms that increase nuclear ERK5—induced ERK5 Small Ubiquitin-related Modifier (SUMO)-2 modification at residues Lys6/Lys22 in cancer cells. Furthermore, mutation of these SUMO sites abolished the ability of ERK5 to translocate to the nucleus and to promote prostatic cancer PC-3 cell proliferation. We also show that overexpression of the SUMO protease SENP2 completely abolished endogenous ERK5 nuclear localization in response to epidermal growth factor (EGF) stimulation. These results allow us to propose a more precise mechanism: in response to MEK5 activation, ERK5 SUMOylation favors the dissociation of Hsp90 from the complex, allowing ERK5 nuclear shuttling and activation of the transcription. Full article
(This article belongs to the Special Issue Targeting MAPK in Cancer)
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Article
Discovery of a Gatekeeper Residue in the C-Terminal Tail of the Extracellular Signal-Regulated Protein Kinase 5 (ERK5)
Int. J. Mol. Sci. 2020, 21(3), 929; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21030929 - 31 Jan 2020
Cited by 5 | Viewed by 1661
Abstract
The extracellular signal-regulated protein kinase 5 (ERK5) is a non-redundant mitogen-activated protein kinase (MAPK) that exhibits a unique C-terminal extension which comprises distinct structural and functional properties. Here, we sought to elucidate the significance of phosphoacceptor sites in the C-terminal transactivation domain of [...] Read more.
The extracellular signal-regulated protein kinase 5 (ERK5) is a non-redundant mitogen-activated protein kinase (MAPK) that exhibits a unique C-terminal extension which comprises distinct structural and functional properties. Here, we sought to elucidate the significance of phosphoacceptor sites in the C-terminal transactivation domain of ERK5. We have found that Thr732 acted as a functional gatekeeper residue controlling C-terminal-mediated nuclear translocation and transcriptional enhancement. Consistently, using a non-bias quantitative mass spectrometry approach, we demonstrated that phosphorylation at Thr732 conferred selectivity for binding interactions of ERK5 with proteins related to chromatin and RNA biology, whereas a number of metabolic regulators were associated with full-length wild type ERK5. Additionally, our proteomic analysis revealed that phosphorylation of the Ser730-Glu-Thr732-Pro motif could occur independently of dual phosphorylation at Thr218-Glu-Tyr220 in the activation loop. Collectively, our results firmly establish the significance of C-terminal phosphorylation in regulating ERK5 function. The post-translational modification of ERK5 on its C-terminal tail might be of particular relevance in cancer cells where ERK5 has be found to be hyperphosphoryated. Full article
(This article belongs to the Special Issue Targeting MAPK in Cancer)
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Review

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Review
Targeting ERK-Hippo Interplay in Cancer Therapy
Int. J. Mol. Sci. 2020, 21(9), 3236; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21093236 - 03 May 2020
Cited by 4 | Viewed by 1362
Abstract
Extracellular signal-regulated kinase (ERK) is a part of the mitogen-activated protein kinase (MAPK) signaling pathway which allows the transduction of various cellular signals to final effectors and regulation of elementary cellular processes. Deregulation of the MAPK signaling occurs under many pathological conditions including [...] Read more.
Extracellular signal-regulated kinase (ERK) is a part of the mitogen-activated protein kinase (MAPK) signaling pathway which allows the transduction of various cellular signals to final effectors and regulation of elementary cellular processes. Deregulation of the MAPK signaling occurs under many pathological conditions including neurodegenerative disorders, metabolic syndromes and cancers. Targeted inhibition of individual kinases of the MAPK signaling pathway using synthetic compounds represents a promising way to effective anti-cancer therapy. Cross-talk of the MAPK signaling pathway with other proteins and signaling pathways have a crucial impact on clinical outcomes of targeted therapies and plays important role during development of drug resistance in cancers. We discuss cross-talk of the MAPK/ERK signaling pathway with other signaling pathways, in particular interplay with the Hippo/MST pathway. We demonstrate the mechanism of cell death induction shared between MAPK/ERK and Hippo/MST signaling pathways and discuss the potential of combination targeting of these pathways in the development of more effective anti-cancer therapies. Full article
(This article belongs to the Special Issue Targeting MAPK in Cancer)
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Review
MAP Kinases Pathways in Gastric Cancer
Int. J. Mol. Sci. 2020, 21(8), 2893; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21082893 - 21 Apr 2020
Cited by 8 | Viewed by 1107
Abstract
Gastric cancer (GC) is turning out today to be one of the most important welfare issues for both Asian and European countries. Indeed, while the vast majority of the disease burden is located in China and in Pacific and East Asia, GC in [...] Read more.
Gastric cancer (GC) is turning out today to be one of the most important welfare issues for both Asian and European countries. Indeed, while the vast majority of the disease burden is located in China and in Pacific and East Asia, GC in European countries still account for about 100,000 deaths per year. With this review article, we aim to focus the attention on one of the most complex cellular pathways involved in GC proliferation, invasion, migration, and metastasis: the MAP kinases. Such large kinases family is to date constantly studied, since their discovery more than 30 years ago, due to the important role that it plays in the regulation of physiological and pathological processes. Interactions with other cellular proteins as well as miRNAs and lncRNAs may modulate their expression influencing the cellular biological features. Here, we summarize the most important and recent studies involving MAPK in GC. At the same time, we need to underly that, differently from cancers arising from other tissues, where MAPK pathways seems to be a gold target for anticancer therapies, GC seems to be unique in any aspect. Our aim is to review the current knowledge in MAPK pathways alterations leading to GC, including H. pylori MAPK-triggering to derail from gastric normal epithelium to GC and to encourage researches involved in MAPK signal transduction, that seems to definitely sustain GC development. Full article
(This article belongs to the Special Issue Targeting MAPK in Cancer)
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Review
The p38 MAPK Signaling Activation in Colorectal Cancer upon Therapeutic Treatments
Int. J. Mol. Sci. 2020, 21(8), 2773; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21082773 - 16 Apr 2020
Cited by 10 | Viewed by 1233
Abstract
Pharmacological treatment of colorectal carcinoma currently proceeds through the administration of a combination of different chemotherapeutic agents. In the case of rectal carcinoma, radiation therapy also represents a therapeutic strategy. In an attempt at translating much-needed new targeted therapy to the clinics, p38 [...] Read more.
Pharmacological treatment of colorectal carcinoma currently proceeds through the administration of a combination of different chemotherapeutic agents. In the case of rectal carcinoma, radiation therapy also represents a therapeutic strategy. In an attempt at translating much-needed new targeted therapy to the clinics, p38 mitogen activated protein kinase (MAPK) inhibitors have been tested in clinical trials involving colorectal carcinoma patients, especially in combination with chemotherapy; however, despite the high expectations raised by a clear involvement of the p38 MAPK pathway in the response to therapeutic treatments, poor results have been obtained so far. In this work, we review recent insights into the exact role of the p38 MAPK pathway in response to currently available therapies for colorectal carcinoma, depicting an intricate scenario in which the p38 MAPK node presents many opportunities, as well as many challenges, for its perspective exploitation for clinical purposes. Full article
(This article belongs to the Special Issue Targeting MAPK in Cancer)
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Review
Current Insights into Combination Therapies with MAPK Inhibitors and Immune Checkpoint Blockade
Int. J. Mol. Sci. 2020, 21(7), 2531; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21072531 - 05 Apr 2020
Cited by 16 | Viewed by 2293
Abstract
The recent development of high-throughput genomics has revolutionized personalized medicine by identifying key pathways and molecular targets controlling tumor progression and survival. Mitogen-activated protein kinase (MAPK) pathways are examples of such targets, and inhibitors against these pathways have shown promising clinical responses in [...] Read more.
The recent development of high-throughput genomics has revolutionized personalized medicine by identifying key pathways and molecular targets controlling tumor progression and survival. Mitogen-activated protein kinase (MAPK) pathways are examples of such targets, and inhibitors against these pathways have shown promising clinical responses in patients with melanoma, non-small-cell lung cancer, colorectal cancer, pancreatic cancer, and thyroid cancer. Although MAPK pathway-targeted therapies have resulted in significant clinical responses in a large proportion of cancer patients, the rate of tumor recurrence is high due to the development of resistance. Conversely, immunotherapies have shown limited clinical responses, but have led to durable tumor regression in patients, and complete responses. Recent evidence indicates that MAPK-targeted therapies may synergize with immune cells, thus providing rationale for the development of combination therapies. Here, we review the current status of ongoing clinical trials investigating MAPK pathway inhibitors, such as BRAF and MAPK/ERK kinase (MEK) inhibitors, in combination with checkpoint inhibitors targeting programmed death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T cell associated antigen-4 (CTLA-4). A better understanding of an individual drug’s mechanism of action, patterns of acquired resistance, and the influence on immune cells will be critical for the development of novel combination therapies. Full article
(This article belongs to the Special Issue Targeting MAPK in Cancer)
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Review
The p38 Pathway: From Biology to Cancer Therapy
Int. J. Mol. Sci. 2020, 21(6), 1913; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21061913 - 11 Mar 2020
Cited by 49 | Viewed by 4342
Abstract
The p38 MAPK pathway is well known for its role in transducing stress signals from the environment. Many key players and regulatory mechanisms of this signaling cascade have been described to some extent. Nevertheless, p38 participates in a broad range of cellular activities, [...] Read more.
The p38 MAPK pathway is well known for its role in transducing stress signals from the environment. Many key players and regulatory mechanisms of this signaling cascade have been described to some extent. Nevertheless, p38 participates in a broad range of cellular activities, for many of which detailed molecular pictures are still lacking. Originally described as a tumor-suppressor kinase for its inhibitory role in RAS-dependent transformation, p38 can also function as a tumor promoter, as demonstrated by extensive experimental data. This finding has prompted the development of specific inhibitors that have been used in clinical trials to treat several human malignancies, although without much success to date. However, elucidating critical aspects of p38 biology, such as isoform-specific functions or its apparent dual nature during tumorigenesis, might open up new possibilities for therapy with unexpected potential. In this review, we provide an extensive description of the main biological functions of p38 and focus on recent studies that have addressed its role in cancer. Furthermore, we provide an updated overview of therapeutic strategies targeting p38 in cancer and promising alternatives currently being explored. Full article
(This article belongs to the Special Issue Targeting MAPK in Cancer)
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Review
Mitogen-Activated Protein Kinase (MAPK) and Obesity-Related Cancer
Int. J. Mol. Sci. 2020, 21(4), 1241; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21041241 - 13 Feb 2020
Cited by 12 | Viewed by 1512
Abstract
Obesity is a major public health concern worldwide. The increased risk of certain types of cancer is now an established deleterious consequence of obesity, although the molecular mechanisms of this are not completely understood. In this review, we aim to explore the links [...] Read more.
Obesity is a major public health concern worldwide. The increased risk of certain types of cancer is now an established deleterious consequence of obesity, although the molecular mechanisms of this are not completely understood. In this review, we aim to explore the links between MAPK signalling and obesity-related cancer. We focus mostly on p38 and JNK MAPK, as the role of ERK remains unclear. These links are seen through the implication of MAPK in obesity-related immune paralysis as well as through effects on the endoplasmic reticulum stress response and activation of aromatase. By way of example, we highlight areas of interest and possibilities for future research in endometrioid endometrial cancer and hepatocellular carcinoma associated with non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) and MAPK. Full article
(This article belongs to the Special Issue Targeting MAPK in Cancer)
Review
Targeting MAPK Signaling in Cancer: Mechanisms of Drug Resistance and Sensitivity
Int. J. Mol. Sci. 2020, 21(3), 1102; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21031102 - 07 Feb 2020
Cited by 82 | Viewed by 3597
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Targeting MAPK in Cancer)
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Review
Beyond Kinase Activity: ERK5 Nucleo-Cytoplasmic Shuttling as a Novel Target for Anticancer Therapy
Int. J. Mol. Sci. 2020, 21(3), 938; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21030938 - 31 Jan 2020
Cited by 6 | Viewed by 1772
Abstract
The importance of mitogen-activated protein kinases (MAPK) in human pathology is underlined by the relevance of abnormalities of MAPK-related signaling pathways to a number of different diseases, including inflammatory disorders and cancer. One of the key events in MAPK signaling, especially with respect [...] Read more.
The importance of mitogen-activated protein kinases (MAPK) in human pathology is underlined by the relevance of abnormalities of MAPK-related signaling pathways to a number of different diseases, including inflammatory disorders and cancer. One of the key events in MAPK signaling, especially with respect to pro-proliferative effects that are crucial for the onset and progression of cancer, is MAPK nuclear translocation and its role in the regulation of gene expression. The extracellular signal-regulated kinase 5 (ERK5) is the most recently discovered classical MAPK and it is emerging as a possible target for cancer treatment. The bigger size of ERK5 when compared to other MAPK enables multiple levels of regulation of its expression and activity. In particular, the phosphorylation of kinase domain and C-terminus, as well as post-translational modifications and chaperone binding, are involved in ERK5 regulation. Likewise, different mechanisms control ERK5 nucleo-cytoplasmic shuttling, underscoring the key role of ERK5 in the nuclear compartment. In this review, we will focus on the mechanisms involved in ERK5 trafficking between cytoplasm and nucleus, and discuss how these processes might be exploited to design new strategies for cancer treatment. Full article
(This article belongs to the Special Issue Targeting MAPK in Cancer)
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Perspective
Prevention of Melanoma Extravasation as a New Treatment Option Exemplified by p38/MK2 Inhibition
Int. J. Mol. Sci. 2020, 21(21), 8344; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218344 - 06 Nov 2020
Viewed by 623
Abstract
Melanoma releases numerous tumor cells into the circulation; however, only a very small fraction of these cells is able to establish distant metastasis. Intravascular survival of circulating tumor cells is limited through hemodynamic forces and by the lack of matrix interactions. The extravasation [...] Read more.
Melanoma releases numerous tumor cells into the circulation; however, only a very small fraction of these cells is able to establish distant metastasis. Intravascular survival of circulating tumor cells is limited through hemodynamic forces and by the lack of matrix interactions. The extravasation step is, thus, of unique importance to establish metastasis. Similar to leukocyte extravasation, this process is under the control of adhesion molecule pairs expressed on melanoma and endothelial cells, and as for leukocytes, ligands need to be adequately presented on cell surfaces. Based on melanoma plasticity, there is considerable heterogeneity even within one tumor and one patient resulting in a mixture of invasive or proliferative cells. The molecular control for this switch is still ill-defined. Recently, the balance between two kinase pathways, p38 and JNK, has been shown to determine growth characteristics of melanoma. While an active JNK pathway induces a proliferative phenotype with reduced invasive features, an active p38/MK2 pathway results in an invasive phenotype and supports the extravasation step via the expression of molecules capable of binding to endothelial integrins. Therapeutic targeting of MK2 to prevent extravasation might reduce metastatic spread. Full article
(This article belongs to the Special Issue Targeting MAPK in Cancer 2.0)
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