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2 pages, 176 KiB

Open AccessEditorial

Non-Canonical Kinases and Substrates in Cancer Progression

by Francisco M. Vega

Cancers 2021, 13(7), 1628; https://doi.org/10.3390/cancers13071628 - 01 Apr 2021

Viewed by 1021

Abstract

Cellular protein kinases remain the target of choice when the intention is to intervene in a particular signaling pathway leading to cancer progression [...] Full article

(This article belongs to the Special Issue Non-canonical Kinases and Substrates in Cancer Progression)

Research

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23 pages, 1735 KiB

Open AccessArticle

The Relevance of the SH2 Domain for c-Src Functionality in Triple-Negative Breast Cancer Cells

by Víctor Mayoral-Varo, María Pilar Sánchez-Bailón, Annarica Calcabrini, Marta García-Hernández, Valerio Frezza, María Elena Martín, Víctor M. González and Jorge Martín-Pérez

Cancers 2021, 13(3), 462; https://doi.org/10.3390/cancers13030462 - 26 Jan 2021

Cited by 8 | Viewed by 2398

Abstract

The role of Src family kinases (SFKs) in human tumors has been always associated with tyrosine kinase activity and much less attention has been given to the SH2 and SH3 adapter domains. Here, we studied the role of the c-Src-SH2 domain in triple-negative [...] Read more.

The role of Src family kinases (SFKs) in human tumors has been always associated with tyrosine kinase activity and much less attention has been given to the SH2 and SH3 adapter domains. Here, we studied the role of the c-Src-SH2 domain in triple-negative breast cancer (TNBC). To this end, SUM159PT and MDA-MB-231 human cell lines were employed as model systems. These cells conditionally expressed, under tetracycline control (Tet-On system), a c-Src variant with point-inactivating mutation of the SH2 adapter domain (R175L). The expression of this mutant reduced the self-renewal capability of the enriched population of breast cancer stem cells (BCSCs), demonstrating the importance of the SH2 adapter domain of c-Src in the mammary gland carcinogenesis. In addition, the analysis of anchorage-independent growth, proliferation, migration, and invasiveness, all processes associated with tumorigenesis, showed that the SH2 domain of c-Src plays a very relevant role in their regulation. Furthermore, the transfection of two different aptamers directed to SH2-c-Src in both SUM159PT and MDA-MB-231 cells induced inhibition of their proliferation, migration, and invasiveness, strengthening the hypothesis that this domain is highly involved in TNBC tumorigenesis. Therefore, the SH2 domain of c-Src could be a promising therapeutic target and combined treatments with inhibitors of c-Src kinase enzymatic activity may represent a new therapeutic strategy for patients with TNBC, whose prognosis is currently very negative. Full article

(This article belongs to the Special Issue Non-canonical Kinases and Substrates in Cancer Progression)

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16 pages, 4207 KiB

Open AccessArticle

Identification of VRK1 as a New Neuroblastoma Tumor Progression Marker Regulating Cell Proliferation

by Ana Colmenero-Repiso, María A. Gómez-Muñoz, Ismael Rodríguez-Prieto, Aida Amador-Álvarez, Kai-Oliver Henrich, Diego Pascual-Vaca, Konstantin Okonechnikov, Eloy Rivas, Frank Westermann, Ricardo Pardal and Francisco M. Vega

Cancers 2020, 12(11), 3465; https://doi.org/10.3390/cancers12113465 - 20 Nov 2020

Cited by 13 | Viewed by 4297

Abstract

Neuroblastoma (NB) is one of the most common pediatric cancers and presents a poor survival rate in affected children. Current pretreatment risk assessment relies on a few known molecular parameters, like the amplification of the oncogene MYCN. However, a better molecular knowledge about [...] Read more.

Neuroblastoma (NB) is one of the most common pediatric cancers and presents a poor survival rate in affected children. Current pretreatment risk assessment relies on a few known molecular parameters, like the amplification of the oncogene MYCN. However, a better molecular knowledge about the aggressive progression of the disease is needed to provide new therapeutical targets and prognostic markers and to improve patients’ outcomes. The human protein kinase VRK1 phosphorylates various signaling molecules and transcription factors to regulate cell cycle progression and other processes in physiological and pathological situations. Using neuroblastoma tumor expression data, tissue microarrays from fresh human samples and patient-derived xenografts (PDXs), we have determined that VRK1 kinase expression stratifies patients according to tumor aggressiveness and survival, allowing the identification of patients with worse outcome among intermediate risk. VRK1 associates with cell cycle signaling pathways in NB and its downregulation abrogates cell proliferation in vitro and in vivo. Through the analysis of ChIP-seq and methylation data from NB tumors, we show that VRK1 is a MYCN gene target, however VRK1 correlates with NB aggressiveness independently of MYCN gene amplification, synergizing with the oncogene to drive NB progression. Our study also suggests that VRK1 inhibition may constitute a novel cell-cycle-targeted strategy for anticancer therapy in neuroblastoma. Full article

(This article belongs to the Special Issue Non-canonical Kinases and Substrates in Cancer Progression)

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21 pages, 5472 KiB

Open AccessArticle

Sunitinib-Containing Carborane Pharmacophore with the Ability to Inhibit Tyrosine Kinases Receptors FLT3, KIT and PDGFR-β, Exhibits Powerful In Vivo Anti-Glioblastoma Activity

by Catalina Alamón, Belén Dávila, María Fernanda García, Carina Sánchez, Mariángeles Kovacs, Emiliano Trias, Luis Barbeito, Martín Gabay, Nidal Zeineh, Moshe Gavish, Francesc Teixidor, Clara Viñas, Marcos Couto and Hugo Cerecetto

Cancers 2020, 12(11), 3423; https://doi.org/10.3390/cancers12113423 - 18 Nov 2020

Cited by 24 | Viewed by 2814

Abstract

Malignant gliomas are the most common malignant and aggressive primary brain tumors in adults, the prognosis being—especially for glioblastomas—extremely poor. There are no effective treatments yet. However, tyrosine kinase receptor (TKR) inhibitors and boron neutron capture therapy (BNCT), together, have been proposed as [...] Read more.

Malignant gliomas are the most common malignant and aggressive primary brain tumors in adults, the prognosis being—especially for glioblastomas—extremely poor. There are no effective treatments yet. However, tyrosine kinase receptor (TKR) inhibitors and boron neutron capture therapy (BNCT), together, have been proposed as future therapeutic strategies. In this sense in our ongoing project of developing new anti-glioblastoma drugs, we identified a sunitinib-carborane hybrid agent, 1, with both in vitro selective cytotoxicity and excellent BNCT-behavior. Consequently, we studied the ability of compound 1 to inhibit TKRs, its promotion of cellular death processes, and its effects on the cell cycle. Moreover, we analyzed some relevant drug-like properties of 1, i.e., mutagenicity and ability to cross the blood–brain barrier. These results encouraged us to perform an in vivo anti-glioblastoma proof of concept assay. It turned out to be a selective FLT3, KIT, and PDGFR-β inhibitor and increased the apoptotic glioma-cell numbers and arrested sub-G1-phase cell cycle. Its in vivo activity in immunosuppressed mice bearing U87 MG human glioblastoma evidenced excellent anti-tumor behavior. Full article

(This article belongs to the Special Issue Non-canonical Kinases and Substrates in Cancer Progression)

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24 pages, 7083 KiB

Open AccessArticle

VRK1 Phosphorylates Tip60/KAT5 and Is Required for H4K16 Acetylation in Response to DNA Damage

by Raúl García-González, Patricia Morejón-García, Ignacio Campillo-Marcos, Marcella Salzano and Pedro A. Lazo

Cancers 2020, 12(10), 2986; https://doi.org/10.3390/cancers12102986 - 15 Oct 2020

Cited by 17 | Viewed by 3801

Abstract

Dynamic remodeling of chromatin requires acetylation and methylation of histones, frequently affecting the same lysine residue. These alternative epigenetic modifications require the coordination of enzymes, writers and erasers, mediating them such as acetylases and deacetylases. In cells in G0/G1, DNA damage induced by [...] Read more.

Dynamic remodeling of chromatin requires acetylation and methylation of histones, frequently affecting the same lysine residue. These alternative epigenetic modifications require the coordination of enzymes, writers and erasers, mediating them such as acetylases and deacetylases. In cells in G0/G1, DNA damage induced by doxorubicin causes an increase in histone H4K16ac, a marker of chromatin relaxation. In this context, we studied the role that VRK1, a chromatin kinase activated by DNA damage, plays in this early step. VRK1 depletion or MG149, a Tip60/KAT5 inhibitor, cause a loss of H4K16ac. DNA damage induces the phosphorylation of Tip60 mediated by VRK1 in the chromatin fraction. VRK1 directly interacts with and phosphorylates Tip60. Furthermore, the phosphorylation of Tip60 induced by doxorubicin is lost by depletion of VRK1 in both ATM +/+ and ATM−/− cells. Kinase-active VRK1, but not kinase-dead VRK1, rescues Tip60 phosphorylation induced by DNA damage independently of ATM. The Tip60 phosphorylation by VRK1 is necessary for the activating acetylation of ATM, and subsequent ATM autophosphorylation, and both are lost by VRK1 depletion. These results support that the VRK1 chromatin kinase is an upstream regulator of the initial acetylation of histones, and an early step in DNA damage responses (DDR). Full article

(This article belongs to the Special Issue Non-canonical Kinases and Substrates in Cancer Progression)

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21 pages, 3436 KiB

Open AccessArticle

GRK2-Dependent HuR Phosphorylation Regulates HIF1α Activation under Hypoxia or Adrenergic Stress

by Clara Reglero, Vanesa Lafarga, Verónica Rivas, Ángela Albitre, Paula Ramos, Susana R. Berciano, Olga Tapia, María L. Martínez-Chantar, Federico Mayor Jr and Petronila Penela

Cancers 2020, 12(5), 1216; https://doi.org/10.3390/cancers12051216 - 13 May 2020

Cited by 14 | Viewed by 4460

Abstract

Adaptation to hypoxia is a common feature in solid tumors orchestrated by oxygen-dependent and independent upregulation of the hypoxia-inducible factor-1α (HIF-1α). We unveiled that G protein-coupled receptor kinase (GRK2), known to be overexpressed in certain tumors, fosters this hypoxic pathway via phosphorylation of [...] Read more.

Adaptation to hypoxia is a common feature in solid tumors orchestrated by oxygen-dependent and independent upregulation of the hypoxia-inducible factor-1α (HIF-1α). We unveiled that G protein-coupled receptor kinase (GRK2), known to be overexpressed in certain tumors, fosters this hypoxic pathway via phosphorylation of the mRNA-binding protein HuR, a central HIF-1α modulator. GRK2-mediated HuR phosphorylation increases the total levels and cytoplasmic shuttling of HuR in response to hypoxia, and GRK2-phosphodefective HuR mutants show defective cytosolic accumulation and lower binding to HIF-1α mRNA in hypoxic Hela cells. Interestingly, enhanced GRK2 and HuR expression correlate in luminal breast cancer patients. GRK2 also promotes the HuR/HIF-1α axis and VEGF-C accumulation in normoxic MCF7 breast luminal cancer cells and is required for the induction of HuR/HIF1-α in response to adrenergic stress. Our results point to a relevant role of the GRK2/HuR/HIF-1α module in the adaptation of malignant cells to tumor microenvironment-related stresses. Full article

(This article belongs to the Special Issue Non-canonical Kinases and Substrates in Cancer Progression)

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17 pages, 2482 KiB

Open AccessArticle

Uncovering Tumour Heterogeneity through PKR and nc886 Analysis in Metastatic Colon Cancer Patients Treated with 5-FU-Based Chemotherapy

by María Belén Ortega-García, Alberto Mesa, Elisa L.J. Moya, Beatriz Rueda, Gabriel Lopez-Ordoño, Javier Ángel García, Verónica Conde, Eduardo Redondo-Cerezo, Javier Luis Lopez-Hidalgo, Gema Jiménez, Macarena Peran, Luis J. Martínez-González, Coral del Val, Igor Zwir, Juan Antonio Marchal and María Ángel García

Cancers 2020, 12(2), 379; https://doi.org/10.3390/cancers12020379 - 07 Feb 2020

Cited by 12 | Viewed by 3465

Abstract

Colorectal cancer treatment has advanced over the past decade. The drug 5-fluorouracil is still used with a wide percentage of patients who do not respond. Therefore, a challenge is the identification of predictive biomarkers. The protein kinase R (PKR also called EIF2AK2) and [...] Read more.

Colorectal cancer treatment has advanced over the past decade. The drug 5-fluorouracil is still used with a wide percentage of patients who do not respond. Therefore, a challenge is the identification of predictive biomarkers. The protein kinase R (PKR also called EIF2AK2) and its regulator, the non-coding pre-mir-nc886, have multiple effects on cells in response to numerous types of stress, including chemotherapy. In this work, we performed an ambispective study with 197 metastatic colon cancer patients with unresectable metastases to determine the relative expression levels of both nc886 and PKR by qPCR, as well as the location of PKR by immunohistochemistry in tumour samples and healthy tissues (plasma and colon epithelium). As primary end point, the expression levels were related to the objective response to first-line chemotherapy following the response evaluation criteria in solid tumours (RECIST) and, as the second end point, with survival at 18 and 36 months. Hierarchical agglomerative clustering was performed to accommodate the heterogeneity and complexity of oncological patients’ data. High expression levels of nc886 were related to the response to treatment and allowed to identify clusters of patients. Although the PKR mRNA expression was not associated with chemotherapy response, the absence of PKR location in the nucleolus was correlated with first-line chemotherapy response. Moreover, a relationship between survival and the expression of both PKR and nc886 in healthy tissues was found. Therefore, this work evaluated the best way to analyse the potential biomarkers PKR and nc886 in order to establish clusters of patients depending on the cancer outcomes using algorithms for complex and heterogeneous data. Full article

(This article belongs to the Special Issue Non-canonical Kinases and Substrates in Cancer Progression)

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Review

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26 pages, 2072 KiB

Open AccessReview

The DYRK Family of Kinases in Cancer: Molecular Functions and Therapeutic Opportunities

by Jacopo Boni, Carlota Rubio-Perez, Nuria López-Bigas, Cristina Fillat and Susana de la Luna

Cancers 2020, 12(8), 2106; https://doi.org/10.3390/cancers12082106 - 29 Jul 2020

Cited by 51 | Viewed by 6364

Abstract

DYRK (dual-specificity tyrosine-regulated kinases) are an evolutionary conserved family of protein kinases with members from yeast to humans. In humans, DYRKs are pleiotropic factors that phosphorylate a broad set of proteins involved in many different cellular processes. These include factors that have been [...] Read more.

DYRK (dual-specificity tyrosine-regulated kinases) are an evolutionary conserved family of protein kinases with members from yeast to humans. In humans, DYRKs are pleiotropic factors that phosphorylate a broad set of proteins involved in many different cellular processes. These include factors that have been associated with all the hallmarks of cancer, from genomic instability to increased proliferation and resistance, programmed cell death, or signaling pathways whose dysfunction is relevant to tumor onset and progression. In accordance with an involvement of DYRK kinases in the regulation of tumorigenic processes, an increasing number of research studies have been published in recent years showing either alterations of DYRK gene expression in tumor samples and/or providing evidence of DYRK-dependent mechanisms that contribute to tumor initiation and/or progression. In the present article, we will review the current understanding of the role of DYRK family members in cancer initiation and progression, providing an overview of the small molecules that act as DYRK inhibitors and discussing the clinical implications and therapeutic opportunities currently available. Full article

(This article belongs to the Special Issue Non-canonical Kinases and Substrates in Cancer Progression)

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17 pages, 1030 KiB

Open AccessEditor’s ChoiceReview

Tyrosine Kinase Inhibitors in Cancer: Breakthrough and Challenges of Targeted Therapy

by Charles Pottier, Margaux Fresnais, Marie Gilon, Guy Jérusalem, Rémi Longuespée and Nor Eddine Sounni

Cancers 2020, 12(3), 731; https://doi.org/10.3390/cancers12030731 - 20 Mar 2020

Cited by 260 | Viewed by 19469

Abstract

Receptor tyrosine kinases (RTKs) are key regulatory signaling proteins governing cancer cell growth and metastasis. During the last two decades, several molecules targeting RTKs were used in oncology as a first or second line therapy in different types of cancer. However, their effectiveness [...] Read more.

Receptor tyrosine kinases (RTKs) are key regulatory signaling proteins governing cancer cell growth and metastasis. During the last two decades, several molecules targeting RTKs were used in oncology as a first or second line therapy in different types of cancer. However, their effectiveness is limited by the appearance of resistance or adverse effects. In this review, we summarize the main features of RTKs and their inhibitors (RTKIs), their current use in oncology, and mechanisms of resistance. We also describe the technological advances of artificial intelligence, chemoproteomics, and microfluidics in elaborating powerful strategies that could be used in providing more efficient and selective small molecules inhibitors of RTKs. Finally, we discuss the interest of therapeutic combination of different RTKIs or with other molecules for personalized treatments, and the challenge for effective combination with less toxic and off-target effects. Full article

(This article belongs to the Special Issue Non-canonical Kinases and Substrates in Cancer Progression)

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