Kinases in Cancer and Other Diseases, 2nd Edition

Topic Information

Dear Colleagues,

Protein kinases comprise a large family of enzymes that catalyze protein phosphorylation. The human genome contains 518 protein kinase genes. Phosphorylation is one of the major mechanisms for regulating various cellular processes, such as proliferation, the apoptosis cell cycle, growth, apoptosis, differentiation, etc. The deregulation of kinase activity can result in significant changes in these processes. Furthermore, deregulated kinases are often oncogenic and essential for the survival and spreading of cancer cells. There are different ways in which kinases are involved in cancers, including misregulated expression and/or amplification, mutation, chromosomal translocation, abnormal phosphorylation, and epigenetic regulation. In order to further investigage these functions, there are various scientific projects assessing the importance of kinases in cancers as well as several other diseases, such as polycystic kidney disease, glomerulonephritis, neurodegeneration, retinal degeneration, lung inflammation, etc. In clinical science the major two kinase investigation routes are (1) using kinases as biomarkers in cancer prognostics and diagnostics and (2) treating cancers with kinase inhibitors and/or monoclonal antibodies. This Topic will highlight current and innovative research achievements in these areas.

Dr. Jonas Cicenas
Dr. Anna M. Czarnecka
Topic Editors

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Participating Journals

Journal Name	Impact Factor	CiteScore	Launched Year	First Decision (median)	APC
Biology biology	3.6	5.7	2012	16.4 Days	CHF 2700	Submit
Biomolecules biomolecules	4.8	9.4	2011	18.4 Days	CHF 2700	Submit
Cancers cancers	4.5	8.0	2009	17.4 Days	CHF 2900	Submit
Cells cells	5.1	9.9	2012	17 Days	CHF 2700	Submit
International Journal of Molecular Sciences ijms	4.9	8.1	2000	16.8 Days	CHF 2900	Submit
Pharmaceuticals pharmaceuticals	4.3	6.1	2004	13.9 Days	CHF 2900	Submit
Kinases and Phosphatases kinasesphosphatases	-	-	2023	15.0 days *	CHF 1000	Submit

* Median value for all MDPI journals in the second half of 2024.

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Published Papers (5 papers)

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All Biology Biomolecules Cancers Cells IJMS Pharmaceuticals Kinases and Phosphatases

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15 pages, 7465 KiB  

Open AccessArticle

Inhibition of NAMPT by PAK4 Inhibitors

by Yiling Wang and Audrey Minden

Int. J. Mol. Sci. 2024, 25(18), 10138; https://doi.org/10.3390/ijms251810138 - 21 Sep 2024

Viewed by 1146

Abstract

The serine/threonine kinase PAK4 plays a crucial role in regulating cell proliferation, survival, migration, and invasion. Overexpression of PAK4 correlates with poor prognosis in some cancers. KPT-9274, a PAK4 inhibitor, significantly reduces the growth of triple-negative breast cancer cells and mammary tumors in [...] Read more.

The serine/threonine kinase PAK4 plays a crucial role in regulating cell proliferation, survival, migration, and invasion. Overexpression of PAK4 correlates with poor prognosis in some cancers. KPT-9274, a PAK4 inhibitor, significantly reduces the growth of triple-negative breast cancer cells and mammary tumors in mouse models, and it also inhibits the growth of several other types of cancer cells. Interestingly, although it was first identified as a PAK4 inhibitor, KPT-9274 was also found to inhibit the enzyme NAMPT (nicotinamide phosphoribosyltransferase), which is crucial for NAD (nicotinamide adenine dinucleotide) synthesis and vital for cellular energy and growth. These results made us question whether growth inhibition in response to KPT-9274 was due to PAK4 inhibition, NAMPT inhibition, or both. To address this, we tested several other PAK4 inhibitors that also inhibit cell growth, to determine whether they also inhibit NAMPT activity. Our findings confirm that multiple PAK4 inhibitors also inhibit NAMPT activity. This was assessed both in cell-free assays and in a breast cancer cell line. Molecular docking studies were also used to help us better understand the mechanism by which PAK4 inhibitors block PAK4 and NAMPT activity, and we identified specific residues on the PAK4 inhibitors that interact with NAMPT and PAK4. Our results suggest that PAK4 inhibitors may have a more complex mechanism of action than previously understood, necessitating further exploration of how they influence cancer cell growth. Full article

(This article belongs to the Topic Kinases in Cancer and Other Diseases, 2nd Edition)

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20 pages, 4106 KiB  

Open AccessArticle

Targeting the p90RSK/MDM2/p53 Pathway Is Effective in Blocking Tumors with Oncogenic Up-Regulation of the MAPK Pathway Such as Melanoma and Lung Cancer

by Immacolata Maietta, Eleonora Viscusi, Stefano Laudati, Giuseppe Iannaci, Antonio D’Antonio, Rosa Marina Melillo, Maria Letizia Motti and Valentina De Falco

Cells 2024, 13(18), 1546; https://doi.org/10.3390/cells13181546 - 14 Sep 2024

Viewed by 1586

Abstract

In most human tumors, the MAPK pathway is constitutively activated. Since p90RSK is downstream of MAPK, it is often hyperactive and capable of phosphorylating oncogenic substrates. We have previously shown that p90RSK phosphorylates MDM2 at S166, promoting p53 degradation in follicular thyroid carcinomas. [...] Read more.

In most human tumors, the MAPK pathway is constitutively activated. Since p90RSK is downstream of MAPK, it is often hyperactive and capable of phosphorylating oncogenic substrates. We have previously shown that p90RSK phosphorylates MDM2 at S166, promoting p53 degradation in follicular thyroid carcinomas. Thus, the inhibition of p90RSK restores p53 expression, which in turn inhibits cell proliferation and promotes apoptosis. In the present study, we demonstrated that the p90RSK/MDM2/p53 pathway proved to be an excellent target in the therapy of tumors with MAPK hyperactivation. For this purpose, we selected p53wt melanoma, lung and medullary thyroid carcinoma cell lines with high activation of p90RSK. In these cell lines, we demonstrated that the p90RSK/MDM2/p53 pathway is implicated in the regulation of the cell cycle and apoptosis through p53-dependent transcriptional control of p21 and Bcl-2. Furthermore, with an immunohistochemical evaluation of primary melanomas and lung tumors, which exhibit highly activated p90RSK compared to corresponding normal tissue, we demonstrated that MDM2 stabilization was associated with p90RSK phosphorylation. The results indicate that p90RSK is able to control the proliferative rate and induction of apoptosis through the regulation of p53wt levels by stabilizing MDM2 in selected tumors with constitutively activated MAPKs, making p90RSK a new attractive target for anticancer therapy. Full article

(This article belongs to the Topic Kinases in Cancer and Other Diseases, 2nd Edition)

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6 pages, 1193 KiB  

Open AccessEditorial

CDK Inhibitors and FDA: Approved and Orphan

by Jonas Cicenas and Jokubas Simkus

Cancers 2024, 16(8), 1555; https://doi.org/10.3390/cancers16081555 - 19 Apr 2024

Cited by 5 | Viewed by 5241

Abstract

The protein kinases are a large family of enzymes which catalyze protein phosphorylation at certain amino acids [...] Full article

(This article belongs to the Topic Kinases in Cancer and Other Diseases, 2nd Edition)

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36 pages, 4065 KiB  

Open AccessReview

The Mitochondrial Connection: The Nek Kinases’ New Functional Axis in Mitochondrial Homeostasis

by Fernanda L. Basei, Ivan Rosa e Silva, Pedro R. Firmino Dias, Camila C. Ferezin, Andressa Peres de Oliveira, Luidy K. Issayama, Livia A. R. Moura, Fernando Riback da Silva and Jörg Kobarg

Cells 2024, 13(6), 473; https://doi.org/10.3390/cells13060473 - 7 Mar 2024

Cited by 1 | Viewed by 2853

Abstract

Mitochondria provide energy for all cellular processes, including reactions associated with cell cycle progression, DNA damage repair, and cilia formation. Moreover, mitochondria participate in cell fate decisions between death and survival. Nek family members have already been implicated in DNA damage response, cilia [...] Read more.

Mitochondria provide energy for all cellular processes, including reactions associated with cell cycle progression, DNA damage repair, and cilia formation. Moreover, mitochondria participate in cell fate decisions between death and survival. Nek family members have already been implicated in DNA damage response, cilia formation, cell death, and cell cycle control. Here, we discuss the role of several Nek family members, namely Nek1, Nek4, Nek5, Nek6, and Nek10, which are not exclusively dedicated to cell cycle-related functions, in controlling mitochondrial functions. Specifically, we review the function of these Neks in mitochondrial respiration and dynamics, mtDNA maintenance, stress response, and cell death. Finally, we discuss the interplay of other cell cycle kinases in mitochondrial function and vice versa. Nek1, Nek5, and Nek6 are connected to the stress response, including ROS control, mtDNA repair, autophagy, and apoptosis. Nek4, in turn, seems to be related to mitochondrial dynamics, while Nek10 is involved with mitochondrial metabolism. Here, we propose that the participation of Neks in mitochondrial roles is a new functional axis for the Nek family. Full article

(This article belongs to the Topic Kinases in Cancer and Other Diseases, 2nd Edition)

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15 pages, 2155 KiB  

Open AccessArticle

The CDK Inhibitor Dinaciclib Improves Cisplatin Response in Nonseminomatous Testicular Cancer: A Preclinical Study

by Elisa Rossini, Mariangela Tamburello, Andrea Abate, Silvia Zini, Giovanni Ribaudo, Alessandra Gianoncelli, Stefano Calza, Francesca Valcamonico, Nazareno R. Suardi, Giuseppe Mirabella, Alfredo Berruti and Sandra Sigala

Cells 2024, 13(5), 368; https://doi.org/10.3390/cells13050368 - 20 Feb 2024

Cited by 2 | Viewed by 1865

Abstract

Background: Most patients with testicular germ cell tumors (GCTs) are treated with cisplatin (CP)-based chemotherapy. However, some of them may develop CP resistance and therefore represent a clinical challenge. Cyclin-dependent kinase 5 (CDK5) is involved in chemotherapy resistance in different types of cancer. [...] Read more.

Background: Most patients with testicular germ cell tumors (GCTs) are treated with cisplatin (CP)-based chemotherapy. However, some of them may develop CP resistance and therefore represent a clinical challenge. Cyclin-dependent kinase 5 (CDK5) is involved in chemotherapy resistance in different types of cancer. Here, we investigated the possible role of CDK5 and other CDKs targeted by dinaciclib in nonseminoma cell models (both CP-sensitive and CP-resistant), evaluating the potential of the CDK inhibitor dinaciclib as a single/combined agent for the treatment of advanced/metastatic testicular cancer (TC). Methods: The effects of dinaciclib and CP on sensitive and resistant NT2/D1 and NCCIT cell viability and proliferation were evaluated using MTT assays and direct count methods. Flow cytometry cell-cycle analysis was performed. The protein expression was assessed via Western blotting. The in vivo experiments were conducted in zebrafish embryos xenografted with TC cells. Results: Among all the CDKs analyzed, CDK5 protein expression was significantly higher in CP-resistant models. Dinaciclib reduced the cell viability and proliferation in each cell model, inducing changes in cell-cycle distribution. In drug combination experiments, dinaciclib enhances the CP effect both in vitro and in the zebrafish model. Conclusions: Dinaciclib, when combined with CP, could be useful for improving nonseminoma TC response to CP. Full article

(This article belongs to the Topic Kinases in Cancer and Other Diseases, 2nd Edition)

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