Kinases in Cancer and Other Diseases

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12 pages, 1670 KiB

Open AccessArticle

Mechanism by Which PF-3758309, a Pan Isoform Inhibitor of p21-Activated Kinases, Blocks Reactivation of HIV-1 Latency

by Benni Vargas, James Boslett, Nathan Yates and Nicolas Sluis-Cremer

Biomolecules 2023, 13(1), 100; https://doi.org/10.3390/biom13010100 - 04 Jan 2023

Viewed by 1647

Abstract

The “block and lock” strategy is one approach that might elicit a sterilizing cure for HIV-1 infection. The “block” refers to a compound’s ability to inhibit latent HIV-1 proviral transcription, while the “lock” refers to its capacity to induce permanent proviral silencing. We previously identified PF-3758309, a pan-isoform inhibitor of p21-activated kinases (PAKs), as a potent inhibitor of HIV-1 latency reversal. The goal of this study was to define the mechanism(s) involved. We found that both 24ST1NLESG cells (a cell line model of HIV-1 latency) and purified CD4+ naïve and central memory T cells express high levels of PAK2 and lower levels of PAK1 and PAK4. Knockdown of PAK1 or PAK2, but not PAK4, in 24ST1NLESG cells resulted in a modest, but statistically significant, decrease in the magnitude of HIV-1 latency reversal. Overexpression of PAK1 significantly increased the magnitude of latency reversal. A phospho-protein array analysis revealed that PF-3758309 down-regulates the NF-κB signaling pathway, which provides the most likely mechanism by which PF-3758309 inhibits latency reversal. Finally, we used cellular thermal shift assays combined with liquid chromatography and mass spectrometry to ascertain whether PF-3758309 off-target binding contributed to its activity. In 24ST1NLESG cells and in peripheral blood mononuclear cells, PF-3758309 bound to mitogen-activated protein kinase 1 and protein kinase A; however, knockdown of either of these kinases did not impact HIV-1 latency reversal. Collectively, our study suggests that PAK1 and PAK2 play a key role in the maintenance of HIV-1 latency. Full article

(This article belongs to the Topic Kinases in Cancer and Other Diseases)

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13 pages, 5677 KiB

Open AccessArticle

Zebrafish Model of Severe Combined Immunodeficiency (SCID) Due to JAK3 Mutation

by Faiza Basheer, Effie Lee, Clifford Liongue and Alister C. Ward

Biomolecules 2022, 12(10), 1521; https://doi.org/10.3390/biom12101521 - 20 Oct 2022

Cited by 5 | Viewed by 2130

Abstract

JAK3 is principally activated by members of the interleukin-2 receptor family and plays an essential role in lymphoid development, with inactivating JAK3 mutations causing autosomal-recessive severe combined immunodeficiency (SCID). This study aimed to generate an equivalent zebrafish model of SCID and to characterize the model across the life-course. Genome editing of zebrafish jak3 created mutants similar to those observed in human SCID. Homozygous jak3 mutants showed reduced embryonic T lymphopoiesis that continued through the larval stage and into adulthood, with B cell maturation and adult NK cells also reduced and neutrophils impacted. Mutant fish were susceptible to lymphoid leukemia. This model has many of the hallmarks of human SCID resulting from inactivating JAK3 mutations and will be useful for a variety of pre-clinical applications. Full article

(This article belongs to the Topic Kinases in Cancer and Other Diseases)

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17 pages, 1838 KiB

Open AccessReview

MAPK Signaling Pathway in Oral Squamous Cell Carcinoma: Biological Function and Targeted Therapy

by Yuxi Cheng, Juan Chen, Yuxin Shi, Xiaodan Fang and Zhangui Tang

Cancers 2022, 14(19), 4625; https://doi.org/10.3390/cancers14194625 - 23 Sep 2022

Cited by 15 | Viewed by 3118

Abstract

Oral squamous cell carcinoma accounts for 95% of human head and neck squamous cell carcinoma cases. It is highly malignant and aggressive, with a poor prognosis and a 5-year survival rate of <50%. In recent years, basic and clinical studies have been performed on the role of the mitogen-activated protein kinase (MAPK) signaling pathway in oral cancer. The MAPK signaling pathway is activated in over 50% of human oral cancer cases. Herein, we review research progress on the MAPK signaling pathway and its potential therapeutic mechanisms and discuss its molecular targeting to explore its potential as a therapeutic strategy for oral squamous cell carcinoma. Full article

(This article belongs to the Topic Kinases in Cancer and Other Diseases)

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17 pages, 3104 KiB

Open AccessArticle

CDK1 Promotes Epithelial–Mesenchymal Transition and Migration of Head and Neck Squamous Carcinoma Cells by Repressing ∆Np63α-Mediated Transcriptional Regulation

by Huimin Chen, Ke Hu, Ying Xie, Yucheng Qi, Wenjuan Li, Yaohui He, Shijie Fan, Wen Liu and Chenghua Li

Int. J. Mol. Sci. 2022, 23(13), 7385; https://doi.org/10.3390/ijms23137385 - 02 Jul 2022

Cited by 5 | Viewed by 2148

Abstract

∆Np63α is a key transcription factor overexpressed in types of squamous cell carcinomas (SCCs), which represses epithelial–mesenchymal transition (EMT) and cell migration. In this study, we found that CDK1 phosphorylates ∆Np63α at the T123 site, impairing its affinity to the target promoters of its downstream genes and its regulation of them in turn. Database analysis revealed that CDK1 is overexpressed in head and neck squamous cell carcinomas (HNSCCs), especially the metastatic HNSCCs, and is negatively correlated with overall survival. We further found that CDK1 promotes the EMT and migration of HNSCC cells by inhibiting ∆Np63α. Altogether, our study identified CDK1 as a novel regulator of ΔNp63α, which can modulate EMT and cell migration in HNSCCs. Our findings will help to elucidate the migration mechanism of HNSCC cells. Full article

(This article belongs to the Topic Kinases in Cancer and Other Diseases)

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10 pages, 2090 KiB

Open AccessCommentary

SGK1 in Cancer: Biomarker and Drug Target

by Jonas Cicenas, Edita Meskinyte-Kausiliene, Vigilijus Jukna, Arnas Rimkus, Jokubas Simkus and Diana Soderholm

Cancers 2022, 14(10), 2385; https://doi.org/10.3390/cancers14102385 - 12 May 2022

Cited by 12 | Viewed by 3469

Abstract

Serum- and glucocorticoid-regulated kinases (SGKs) are members of the AGC family of serine/threonine kinases, consisting of three isoforms: SGK1, SGK2, and SGK3. SGK1 was initially cloned as a gene transcriptionally stimulated by serum and glucocorticoids in rat mammary tumor cells. It is upregulated in some cancers and downregulated in others. SGK1 increases tumor cell survival, adhesiveness, invasiveness, motility, and epithelial to mesenchymal transition. It stimulates tumor growth by mechanisms such as activation of K⁺ channels and Ca²⁺ channels, Na⁺/H⁺ exchanger, amino acid and glucose transporters, downregulation of Foxo3a and p53, and upregulation of β-catenin and NFκB. This chapter focuses on major aspects of SGK1 involvement in cancer, its use as biomarker as well as potential therapeutic target. Full article

(This article belongs to the Topic Kinases in Cancer and Other Diseases)

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20 pages, 2360 KiB

Open AccessReview

Discovery of Raf Family Is a Milestone in Deciphering the Ras-Mediated Intracellular Signaling Pathway

by Jingtong Zhao and Zhijun Luo

Int. J. Mol. Sci. 2022, 23(9), 5158; https://doi.org/10.3390/ijms23095158 - 05 May 2022

Cited by 16 | Viewed by 3713

Abstract

The Ras-Raf-MEK-ERK signaling pathway, the first well-established MAPK pathway, plays essential roles in cell proliferation, survival, differentiation and development. It is activated in over 40% of human cancers owing to mutations of Ras, membrane receptor tyrosine kinases and other oncogenes. The Raf family consists of three isoforms, A-Raf, B-Raf and C-Raf. Since the first discovery of a truncated mutant of C-Raf as a transforming oncogene carried by a murine retrovirus, forty years of extensive studies have provided a wealth of information on the mechanisms underlying the activation, regulation and biological functions of the Raf family. However, the mechanisms by which activation of A-Raf and C-Raf is accomplished are still not completely understood. In contrast, B-Raf can be easily activated by binding of Ras-GTP, followed by cis-autophosphorylation of the activation loop, which accounts for the fact that this isoform is frequently mutated in many cancers, especially melanoma. The identification of oncogenic B-Raf mutations has led to accelerated drug development that targets Raf signaling in cancer. However, the effort has not proved as effective as anticipated, inasmuch as the mechanism of Raf activation involves multiple steps, factors and phosphorylation of different sites, as well as complex interactions between Raf isoforms. In this review, we will focus on the physiological complexity of the regulation of Raf kinases and their connection to the ERK phosphorylation cascade and then discuss the role of Raf in tumorigenesis and the clinical application of Raf inhibitors in the treatment of cancer. Full article

(This article belongs to the Topic Kinases in Cancer and Other Diseases)

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17 pages, 9090 KiB

Open AccessArticle

The Potential Role of Phenolic Acids from Salvia miltiorrhiza and Cynara scolymus and Their Derivatives as JAK Inhibitors: An In Silico Study

by Hui-Jun Liao and Jason T. C. Tzen

Int. J. Mol. Sci. 2022, 23(7), 4033; https://doi.org/10.3390/ijms23074033 - 05 Apr 2022

Cited by 2 | Viewed by 3384

Abstract

JAK inhibition is a new strategy for treating autoimmune and inflammatory diseases. Previous studies have shown the immunoregulatory and anti-inflammatory effects of Salvia miltiorrhiza and Cynara scolymus and suggest that the bioactivity of their phenolic acids involves the JAK-STAT pathway, but it is unclear whether these effects occur through JAK inhibition. The JAK binding affinities obtained by docking Rosmarinic acid (RosA), Salvianolic acid A (SalA), Salvianolic acid C (SalC), Lithospermic acid, Salvianolic acid B and Cynarin (CY) to JAK (PDB: 6DBN) with AutoDock Vina are −8.8, −9.8, −10.7, −10.0, −10.3 and −9.7 kcal/mol, respectively. Their predicted configurations enable hydrogen bonding with the hinge region and N- and C-terminal lobes of the JAK kinase domain. The benzofuran core of SalC, the compound with the greatest binding affinity, sits near Leu959, such as Tofacitinib’s pyrrolopyrimidine. A SalC derivative with a binding affinity of −12.2 kcal/mol was designed while maintaining this relationship. The docking results show follow-up studies of these phenolic acids as JAK inhibitors may be indicated. Furthermore, derivatives of SalC, RosA, CY and SalA can yield better binding affinity or bioavailability scores, indicating that their structures may be suitable as scaffolds for the design of new JAK inhibitors. Full article

(This article belongs to the Topic Kinases in Cancer and Other Diseases)

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17 pages, 3182 KiB

Open AccessArticle

Converged DNA Damage Response Renders Human Hepatocellular Carcinoma Sensitive to CDK7 Inhibition

by Guiqin Xie, Ailin Zhu and Xinbin Gu

Cancers 2022, 14(7), 1714; https://doi.org/10.3390/cancers14071714 - 28 Mar 2022

Cited by 3 | Viewed by 1910

Abstract

Hepatocellular carcinoma (HCC) is a lethal malignancy with high mortality. The inhibition of cyclin-dependent kinase 7 (CDK7) activity has shown therapeutic efficacy in HCC. However, the underlying molecular mechanisms remain elusive. Here, we show that three HCC lines, HepG2, Hep3B, and SK-Hep-1, were highly susceptible to the CDK7 inhibitor THZ1. In mouse models, THZ1 effectively reduced HepG2 tumor growth and tumor weight. THZ1 arrested cell cycle and triggered MYC-related apoptosis in HepG2. To evaluate how MYC protein levels affected THZ1-induced apoptotic cell death, we overexpressed MYC in HepG2 and found that exogenously overexpressed MYC promoted cell cycle progression and increased cells in the S phase. THZ1 drastically engendered the apoptosis of MYC-overexpressing HepG2 cells in the S and G2/M phases. Importantly, transcription-inhibition-induced apoptosis is associated with DNA damage, and exogenous MYC expression further enhanced the THZ1-induced DNA damage response in MYC-overexpressing HepG2 cells. Consistently, in the HepG2 xenografts, THZ1 treatment was associated with DNA-damage-induced cell death. Together, our data indicate that the converged effect of MYC-promoted cell cycle progression and CDK7 inhibition by THZ1 confers the hypersensitivity of HCC to DNA-damage-induced cell death. Our findings may suggest a new therapeutic strategy of THZ1 against HCC. Full article

(This article belongs to the Topic Kinases in Cancer and Other Diseases)

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Journal Name	Impact Factor	CiteScore	Launched Year	First Decision (median)	APC
Biomolecules biomolecules	5.5	8.3	2011	16.9 Days	CHF 2700
Cancers cancers	5.2	7.4	2009	17.9 Days	CHF 2900
Current Oncology curroncol	2.6	2.6	1994	18 Days	CHF 2200
International Journal of Molecular Sciences ijms	5.6	7.8	2000	16.3 Days	CHF 2900
Onco onco	-	-	2021	18.3 Days	CHF 1000

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