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18 pages, 3895 KiB

Open AccessArticle

Horizontal Combination of MEK and PI3K/mTOR Inhibition in BRAF Mutant Tumor Cells with or without Concomitant PI3K Pathway Mutations

by Dominika Rittler, Eszter Molnár, Marcell Baranyi, Tamás Garay, Luca Hegedűs, Clemens Aigner, József Tóvári, József Tímár and Balázs Hegedűs

Int. J. Mol. Sci. 2020, 21(20), 7649; https://doi.org/10.3390/ijms21207649 - 16 Oct 2020

Cited by 6 | Viewed by 2537

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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18 pages, 2750 KiB

Open AccessArticle

SUMOylation Is Required for ERK5 Nuclear Translocation and ERK5-Mediated Cancer Cell Proliferation

by Tatiana Erazo, Sergio Espinosa-Gil, Nora Diéguez-Martínez, Néstor Gómez and Jose M Lizcano

Int. J. Mol. Sci. 2020, 21(6), 2203; https://doi.org/10.3390/ijms21062203 - 23 Mar 2020

Cited by 24 | Viewed by 4615

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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16 pages, 4161 KiB

Open AccessArticle

Discovery of a Gatekeeper Residue in the C-Terminal Tail of the Extracellular Signal-Regulated Protein Kinase 5 (ERK5)

by Adam J. Pearson, Paul Fullwood, Gabriela Toro Tapia, Ian Prise, Michael P. Smith, Qiuping Xu, Allan Jordan, Emanuele Giurisato, Alan J. Whitmarsh, Chiara Francavilla and Cathy Tournier

Int. J. Mol. Sci. 2020, 21(3), 929; https://doi.org/10.3390/ijms21030929 - 31 Jan 2020

Cited by 9 | Viewed by 4958

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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17 pages, 1721 KiB

Open AccessReview

Targeting ERK-Hippo Interplay in Cancer Therapy

by Karel Vališ and Petr Novák

Int. J. Mol. Sci. 2020, 21(9), 3236; https://doi.org/10.3390/ijms21093236 - 03 May 2020

Cited by 20 | Viewed by 4430

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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17 pages, 1227 KiB

Open AccessReview

MAP Kinases Pathways in Gastric Cancer

by Lucia Magnelli, Nicola Schiavone, Fabio Staderini, Alessio Biagioni and Laura Papucci

Int. J. Mol. Sci. 2020, 21(8), 2893; https://doi.org/10.3390/ijms21082893 - 21 Apr 2020

Cited by 44 | Viewed by 4220

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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13 pages, 1224 KiB

Open AccessReview

The p38 MAPK Signaling Activation in Colorectal Cancer upon Therapeutic Treatments

by Angelina Pranteda, Valentina Piastra, Lorenzo Stramucci, Deborah Fratantonio and Gianluca Bossi

Int. J. Mol. Sci. 2020, 21(8), 2773; https://doi.org/10.3390/ijms21082773 - 16 Apr 2020

Cited by 37 | Viewed by 5063

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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34 pages, 880 KiB

Open AccessReview

Current Insights into Combination Therapies with MAPK Inhibitors and Immune Checkpoint Blockade

by Min Hwa Shin, Jiyoung Kim, Siyoung A. Lim, Jeongsoo Kim and Kyung-Mi Lee

Int. J. Mol. Sci. 2020, 21(7), 2531; https://doi.org/10.3390/ijms21072531 - 05 Apr 2020

Cited by 57 | Viewed by 6850

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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18 pages, 1683 KiB

Open AccessReview

The p38 Pathway: From Biology to Cancer Therapy

by Adrián Martínez-Limón, Manel Joaquin, María Caballero, Francesc Posas and Eulàlia de Nadal

Int. J. Mol. Sci. 2020, 21(6), 1913; https://doi.org/10.3390/ijms21061913 - 11 Mar 2020

Cited by 216 | Viewed by 16654

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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19 pages, 295 KiB

Open AccessReview

Mitogen-Activated Protein Kinase (MAPK) and Obesity-Related Cancer

by Fionán Donohoe, Michael Wilkinson, Eva Baxter and Donal J. Brennan

Int. J. Mol. Sci. 2020, 21(4), 1241; https://doi.org/10.3390/ijms21041241 - 13 Feb 2020

Cited by 50 | Viewed by 4889

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)

29 pages, 1817 KiB

Open AccessReview

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

by Shannon Lee, Jens Rauch and Walter Kolch

Int. J. Mol. Sci. 2020, 21(3), 1102; https://doi.org/10.3390/ijms21031102 - 07 Feb 2020

Cited by 426 | Viewed by 17775

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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17 pages, 857 KiB

Open AccessReview

Beyond Kinase Activity: ERK5 Nucleo-Cytoplasmic Shuttling as a Novel Target for Anticancer Therapy

by Alessandro Tubita, Zoe Lombardi, Ignazia Tusa, Persio Dello Sbarba and Elisabetta Rovida

Int. J. Mol. Sci. 2020, 21(3), 938; https://doi.org/10.3390/ijms21030938 - 31 Jan 2020

Cited by 23 | Viewed by 5382

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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