Topical Collection "Protein Kinases and Cancer"

A topical collection in Pharmaceuticals (ISSN 1424-8247). This collection belongs to the section "Pharmacology".

Editors

Prof. Dr. Khalil Ahmed
Website
Collection Editor
Minneapolis V.A. Health Care System, and Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA
Interests: protein kinases; protein kinase CK2; prostate cancer; androgens; cancer; head and neck cancer; signaling; protein kinases as targets for therapy; cancer therapy; nuclear matrix; chromatin; intracellular shuttling; apoptosis; mitochondria; cell death; cell calcium
Dr. Janeen Trembley
Website
Collection Editor
Dept. of Laboratory Medicine and Pathology, University of Minnesota, Health Science Specialist, Research Service (151), Room 4P-123, Minneapolis VA, Health Care System, 1 Veterans Dr. Minneapolis, MN 55417, USA
Interests: CK2; CDK11; kinase; Cyclins and CDKs; prostate cancer; breast cancer; melanoma; transcription; cell cycle

Topical Collection Information

Dear Colleagues,

During the latter part of the twentieth century, it has continuously been recognized that protein kinases represent a large group of enzymes involved in the phosphorylation of proteins at various sites, thereby altering their functional activities. Protein phosphorylation has emerged as a major post-translation modification encountered by proteins occurring in normal, as well as in abnormal, cell functions. Virtually every aspect of biology is affected by activity of protein kinases. Diverse protein kinases modify proteins largely at serine, threonine, and tyrosine, although other phosphorylation sites are also known. Importantly, a protein may be modified by several protein kinases at the same sites, as well as at multiple sites by different kinases, thereby resulting in complex regulation of the function of a particular protein.

Because of the vast involvement of protein kinases in cell biological functions and their role in various disease states, it stands to reason that protein kinases have attracted much attention as possible targets for therapeutic intervention. In this regard, the role of dysregulated function of protein kinases in cancer has attracted particular consideration and there is a large body of ongoing investigations in this subject area as many different protein kinases are implicated in cancer development and survival. The involvement of protein kinases in cancer is also of focal interest because they serve as existing and potential targets for cancer therapy, and this is also a highly active area of research.  

The present Special Issue of Pharmaceuticals is specially dedicated to “Protein Kinases and Cancer”, and represents a compendium of manuscripts and review articles involving different protein kinases with respect to their biological function in various cancers and their potential as therapeutic targets. Pharmaceuticals has previously published a Special Issue dealing with Protein Kinase CK2 and Cancer; you may refer to:https://www.mdpi.com/journal/pharmaceuticals/special_issues/protein_kinase_CK2. However, the present issue includes a broader range of topics covering Protein Kinases and Cancer. We sincerely hope that you will be able to contribute a research manuscript or review article dealing with your research in this area of investigation. The quality of the publications will be ensured by peer review of all the manuscripts prior to their publication.

We look forward to your participation in this endeavor.

Prof. Dr. Khalil Ahmed
Dr. Janeen Trembley
Guest Editors

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 collection 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.

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1000 CHF (Swiss Francs). 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

  • Protein kinases
  • Cancer biology
  • Cancer therapy
  • Signaling
  • Protein kinases as target for cancer therapy

Published Papers (8 papers)

2020

Jump to: 2019

Open AccessArticle
Cyclin-Dependent Kinase and Antioxidant Gene Expression in Cancers with Poor Therapeutic Response
Pharmaceuticals 2020, 13(2), 26; https://doi.org/10.3390/ph13020026 - 05 Feb 2020
Abstract
Pancreatic cancer, hepatocellular carcinoma (HCC), and mesothelioma are treatment-refractory cancers, and patients afflicted with these cancers generally have a very poor prognosis. The genomics of these tumors were analyzed as part of The Cancer Genome Atlas (TCGA) project. However, these analyses are an [...] Read more.
Pancreatic cancer, hepatocellular carcinoma (HCC), and mesothelioma are treatment-refractory cancers, and patients afflicted with these cancers generally have a very poor prognosis. The genomics of these tumors were analyzed as part of The Cancer Genome Atlas (TCGA) project. However, these analyses are an overview and may miss pathway interactions that could be exploited for therapeutic targeting. In this study, the TCGA Pan-Cancer datasets were queried via cBioPortal for correlations among mRNA expression of key genes in the cell cycle and mitochondrial (mt) antioxidant defense pathways. Here we describe these correlations. The results support further evaluation to develop combination treatment strategies that target these two critical pathways in pancreatic cancer, hepatocellular carcinoma, and mesothelioma. Full article
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Open AccessReview
Mitogen-Activated Protein Kinase Inhibitors and T-Cell-Dependent Immunotherapy in Cancer
Pharmaceuticals 2020, 13(1), 9; https://doi.org/10.3390/ph13010009 - 07 Jan 2020
Cited by 2
Abstract
Mitogen-activated protein kinase (MAPK) signaling networks serve to regulate a wide range of physiologic and cancer-associated cell processes. For instance, a variety of oncogenic mutations often lead to hyperactivation of MAPK signaling, thereby enhancing tumor cell proliferation and disease progression. As such, several [...] Read more.
Mitogen-activated protein kinase (MAPK) signaling networks serve to regulate a wide range of physiologic and cancer-associated cell processes. For instance, a variety of oncogenic mutations often lead to hyperactivation of MAPK signaling, thereby enhancing tumor cell proliferation and disease progression. As such, several components of the MAPK signaling network have been proposed as viable targets for cancer therapy. However, the contributions of MAPK signaling extend well beyond the tumor cells, and several MAPK effectors have been identified as key mediators of the tumor microenvironment (TME), particularly with respect to the local immune infiltrate. In fact, a blockade of various MAPK signals has been suggested to fundamentally alter the interaction between tumor cells and T lymphocytes and have been suggested a potential adjuvant to immune checkpoint inhibition in the clinic. Therefore, in this review article, we discuss the various mechanisms through which MAPK family members contribute to T-cell biology, as well as circumstances in which MAPK inhibition may potentiate or limit cancer immunotherapy. Full article
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2019

Jump to: 2020

Open AccessArticle
Prostate-Derived ETS Factor (PDEF) Modulates Yes Associated Protein 1 (YAP1) in Prostate Cancer Cells: A Potential Cross-Talk between PDEF and Hippo Signaling
Pharmaceuticals 2019, 12(4), 181; https://doi.org/10.3390/ph12040181 - 10 Dec 2019
Abstract
PDEF (prostate-derived ETS factor, also known as SAM-pointed domain containing ETS transcription factor (SPDEF)) is expressed in luminal epithelial cells of the prostate gland and associates with luminal phenotype. The Hippo pathway regulates cell growth/proliferation, cellular homeostasis, and organ development by modulating phosphorylation [...] Read more.
PDEF (prostate-derived ETS factor, also known as SAM-pointed domain containing ETS transcription factor (SPDEF)) is expressed in luminal epithelial cells of the prostate gland and associates with luminal phenotype. The Hippo pathway regulates cell growth/proliferation, cellular homeostasis, and organ development by modulating phosphorylation of its downstream effectors. In previous studies, we observed decreased levels of PDEF during prostate cancer progression. In the present study, we evaluated the effects of the expression of PDEF on total/phosphoprotein levels of YAP1 (a downstream effector of the Hippo pathway). We observed that the PC3 and DU145 cells transfected with PDEF (PDEF-PC3 and PDEF-DU145) showed an increased phospho-YAP1 (Ser127) and total YAP1 levels as compared to the respective PC3 vector control (VC-PC3) and DU145 vector control cells (VC-DU145). We also observed an increased cytoplasmic YAP1 levels in PDEF-PC3 cells as compared to VC-PC3 cells. Moreover, our gene set enrichment analysis (GSEA) of mRNA expression in PDEF-PC3 and VC-PC3 cells revealed that PDEF resulted in inhibition of YAP1 target genes, directly demonstrating that PDEF plays a critical role in modulating YAP1 activity, and by extension in the regulation of the Hippo pathway. We also observed a decrease in YAP1 mRNA levels in prostate cancer tissues as compared to normal prostate tissues. Our analysis of multiple publicly available clinical cohorts revealed a gradual decrease in YAP1 mRNA expression during prostate cancer progression and metastasis. This decrease was similar to the decrease in PDEF levels, which we had reported earlier, and we observed a direct correlation between PDEF and YAP1 expression in CRPC data set. To the best of our knowledge, these results provide the first demonstration of inhibiting YAP1 activity by PDEF in any system and suggest a cross-talk between PDEF and the Hippo signaling pathway. Full article
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Open AccessReview
CDK8-Novel Therapeutic Opportunities
Pharmaceuticals 2019, 12(2), 92; https://doi.org/10.3390/ph12020092 - 19 Jun 2019
Cited by 2
Abstract
Improvements in cancer therapy frequently stem from the development of new small-molecule inhibitors, paralleled by the identification of biomarkers that can predict the treatment response. Recent evidence supports the idea that cyclin-dependent kinase 8 (CDK8) may represent a potential drug target for breast [...] Read more.
Improvements in cancer therapy frequently stem from the development of new small-molecule inhibitors, paralleled by the identification of biomarkers that can predict the treatment response. Recent evidence supports the idea that cyclin-dependent kinase 8 (CDK8) may represent a potential drug target for breast and prostate cancer, although no CDK8 inhibitors have entered the clinics. As the available inhibitors have been recently reviewed, we focus on the biological functions of CDK8 and provide an overview of the complexity of CDK8-dependent signaling throughout evolution and CDK8-dependent effects that may open novel treatment avenues. Full article
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Open AccessArticle
CK2 Pro-Survival Role in Prostate Cancer Is Mediated via Maintenance and Promotion of Androgen Receptor and NFκB p65 Expression
Pharmaceuticals 2019, 12(2), 89; https://doi.org/10.3390/ph12020089 - 14 Jun 2019
Cited by 1
Abstract
The prosurvival protein kinase CK2, androgen receptor (AR), and nuclear factor kappa B (NFκB) interact in the function of prostate cells, and there is evidence of crosstalk between these signals in the pathobiology of prostate cancer (PCa). As CK2 is elevated in PCa, [...] Read more.
The prosurvival protein kinase CK2, androgen receptor (AR), and nuclear factor kappa B (NFκB) interact in the function of prostate cells, and there is evidence of crosstalk between these signals in the pathobiology of prostate cancer (PCa). As CK2 is elevated in PCa, and AR and NFκB are involved in the development and progression of prostate cancer, we investigated their interaction in benign and malignant prostate cells in the presence of altered CK2 expression. Our results show that elevation of CK2 levels caused increased levels of AR and NFκB p65 in prostate cells of different phenotypes. Analysis of TCGA PCa data indicated that AR and CK2α RNA expression are strongly correlated. Small molecule inhibition or molecular down-regulation of CK2 caused reduction in AR mRNA expression and protein levels in PCa cells and in orthotopic xenograft tumors by various pathways. Among these, regulation of AR protein stability plays a unifying role in CK2 maintenance of AR protein levels. Our results show induction of various endoplasmic reticulum stress signals after CK2 inhibition, which may play a role in the PCa cell death response. Of note, CK2 inhibition caused loss of cell viability in both parental and enzalutamide-resistant castrate-resistant PCa cells. The present work elucidates the specific link of CK2 to the pathogenesis of PCa in association with AR and NFκB expression; further, the observation that inhibition of CK2 can exert a growth inhibitory effect on therapy-resistant PCa cells emphasizes the potential utility of CK2 inhibition in patients who are on enzalutamide treatment for advanced cancer. Full article
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Open AccessArticle
CDK11 Loss Induces Cell Cycle Dysfunction and Death of BRAF and NRAS Melanoma Cells
Pharmaceuticals 2019, 12(2), 50; https://doi.org/10.3390/ph12020050 - 02 Apr 2019
Cited by 2
Abstract
Cyclin dependent kinase 11 (CDK11) is a protein kinase that regulates RNA transcription, pre-mRNA splicing, mitosis, and cell death. Targeting of CDK11 expression levels is effective in the experimental treatment of breast and other cancers, but these data are lacking in melanoma. To [...] Read more.
Cyclin dependent kinase 11 (CDK11) is a protein kinase that regulates RNA transcription, pre-mRNA splicing, mitosis, and cell death. Targeting of CDK11 expression levels is effective in the experimental treatment of breast and other cancers, but these data are lacking in melanoma. To understand CDK11 function in melanoma, we evaluated protein and RNA levels of CDK11, Cyclin L1 and Cyclin L2 in benign melanocytes and BRAF- as well as NRAS-mutant melanoma cell lines. We investigated the effectiveness of reducing expression of this survival kinase using RNA interference on viability, clonal survival, and tumorsphere formation in melanoma cell lines. We examined the impact of CDK11 loss in BRAF-mutant melanoma on more than 700 genes important in cancer signaling pathways. Follow-up analysis evaluated how CDK11 loss alters cell cycle function in BRAF- and NRAS-mutant melanoma cells. We present data on CDK11, CCNL1 and CCNL2 mRNA expression in melanoma patients, including prognosis for survival. In sum, we found that CDK11 is necessary for melanoma cell survival, and a major impact of CDK11 loss in melanoma is to cause disruption of the cell cycle distribution with accumulation of G1- and loss of G2/M-phase cancer cells. Full article
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Open AccessReview
The Multi-Functional Calcium/Calmodulin Stimulated Protein Kinase (CaMK) Family: Emerging Targets for Anti-Cancer Therapeutic Intervention
Pharmaceuticals 2019, 12(1), 8; https://doi.org/10.3390/ph12010008 - 07 Jan 2019
Cited by 10
Abstract
The importance of Ca2+ signalling in key events of cancer cell function and tumour progression, such as proliferation, migration, invasion and survival, has recently begun to be appreciated. Many cellular Ca2+-stimulated signalling cascades utilise the intermediate, calmodulin (CaM). The Ca [...] Read more.
The importance of Ca2+ signalling in key events of cancer cell function and tumour progression, such as proliferation, migration, invasion and survival, has recently begun to be appreciated. Many cellular Ca2+-stimulated signalling cascades utilise the intermediate, calmodulin (CaM). The Ca2+/CaM complex binds and activates a variety of enzymes, including members of the multifunctional Ca2+/calmodulin-stimulated protein kinase (CaMK) family. These enzymes control a broad range of cancer-related functions in a multitude of tumour types. Herein, we explore the cancer-related functions of these kinases and discuss their potential as targets for therapeutic intervention. Full article
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Open AccessReview
Natural Compounds and Derivatives as Ser/Thr Protein Kinase Modulators and Inhibitors
Pharmaceuticals 2019, 12(1), 4; https://doi.org/10.3390/ph12010004 - 01 Jan 2019
Cited by 3
Abstract
The need for new drugs is compelling, irrespective of the disease. Focusing on medical problems in the Western countries, heart disease and cancer are at the moment predominant illnesses. Owing to the fact that ~90% of all 21,000 cellular proteins in humans are [...] Read more.
The need for new drugs is compelling, irrespective of the disease. Focusing on medical problems in the Western countries, heart disease and cancer are at the moment predominant illnesses. Owing to the fact that ~90% of all 21,000 cellular proteins in humans are regulated by phosphorylation/dephosphorylation it is not surprising that the enzymes catalysing these reactions (i.e., protein kinases and phosphatases, respectively) have attracted considerable attention in the recent past. Protein kinases are major team players in cell signalling. In tumours, these enzymes are found to be mutated disturbing the proper function of signalling pathways and leading to uncontrolled cellular growth and sustained malignant behaviour. Hence, the search for small-molecule inhibitors targeting the altered protein kinase molecules in tumour cells has become a major research focus in the academia and pharmaceutical companies. Full article
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