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17 pages, 1639 KiB  
Article
Tricyclic Isatin Derivatives as Anti-Inflammatory Compounds with High Kinase Binding Affinity
by Alexander V. Uvarov, Igor A. Schepetkin, Mark T. Quinn and Andrei I. Khlebnikov
Molecules 2025, 30(14), 2914; https://doi.org/10.3390/molecules30142914 - 10 Jul 2025
Viewed by 350
Abstract
Oximes have been reported to exhibit useful pharmaceutical properties, including compounds with anticancer, anti-arthritis, antibacterial, and neuroprotective activities. Many oximes are kinase inhibitors and have been shown to inhibit various kinases. Herein, a panel of oxime derivatives of tricyclic isatins was synthesized and [...] Read more.
Oximes have been reported to exhibit useful pharmaceutical properties, including compounds with anticancer, anti-arthritis, antibacterial, and neuroprotective activities. Many oximes are kinase inhibitors and have been shown to inhibit various kinases. Herein, a panel of oxime derivatives of tricyclic isatins was synthesized and evaluated for inhibition of cellular inflammatory responses and binding affinity to several kinases. Compounds 5a and 5d (a.k.a. NS-102), which have an unsubstituted oxime group, inhibited lipopolysaccharide (LPS)-induced nuclear factor-κB/activating protein 1 (NF-κB/AP-1) transcriptional activity in human THP-1Blue monocytic cells and interleukin-6 (IL-6) production in human MonoMac-6 monocytic cells, with IC50 values in the micromolar range. These compounds also inhibited LPS-induced production of several other proinflammatory cytokines, including IL-1α, IL-1β, monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor (TNF) in MonoMac-6 cells. Compounds 5a and 5d exhibited nanomolar/submicromolar binding affinity toward several kinase targets. The most potent inhibitor, 5d (3-(hydroxyimino)-5-nitro-1,3,6,7,8,9-hexahydro-2H-benzo[g]indol-2-one), demonstrated high binding affinity for 12 kinases, including DYRK1A, DYRK1B, PIM1, Haspin, HIPK1-3, IRAK1, NEK10, and DAPK1-3. Molecular modeling suggested modes of binding interaction of selected compounds in the DYRK1A and PIM1 catalytic sites that agreed with the experimental binding data. Our results demonstrate that tricyclic isatin oximes could be potential candidates for developing anti-inflammatory drugs with neuroprotective effects for treating neurodegenerative diseases. Full article
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23 pages, 8524 KiB  
Article
MCM4 as Potential Metastatic Biomarker in Lung Adenocarcinoma
by Hung-Chih Lai, Ju-Fang Liu, Tsung-Ming Chang and Thai-Yen Ling
Diagnostics 2025, 15(12), 1555; https://doi.org/10.3390/diagnostics15121555 - 18 Jun 2025
Viewed by 598
Abstract
Background: Lung adenocarcinoma (LUAD) is the most common subtype of non-small-cell lung cancer and is frequently diagnosed at advanced stages with metastasis, contributing to its poor prognosis. Identifying key metastasis-related biomarkers is critical for improving early diagnosis and therapeutic targeting. Methods: We analyzed [...] Read more.
Background: Lung adenocarcinoma (LUAD) is the most common subtype of non-small-cell lung cancer and is frequently diagnosed at advanced stages with metastasis, contributing to its poor prognosis. Identifying key metastasis-related biomarkers is critical for improving early diagnosis and therapeutic targeting. Methods: We analyzed four GEO microarray datasets (GSE32863, GSE27262, GSE40275, and GSE33356) and TCGA data to identify differentially expressed genes (DEGs) in LUAD. Functional enrichment of DEGs was analyzed using Gene Ontology, Kyoto Encyclopedia of Genes and Genomes analysis, and a Cancer Hallmark Enrichment Plot. Hub gene analysis was conducted using Cytoscape. Hub genes were evaluated for their expression, prognostic significance (via the Kaplan–Meier plotter), and clinical correlation using additional platforms (TCGA, Lung Cancer Explorer, TNMplot, and the Human Protein Atlas). Results: A total of 333 consistently dysregulated DEGs were identified, enriched in pathways related to metastasis, including angiogenesis, immune escape, and ECM interaction. Ten hub genes (AURKA, TOP2A, CCNB2, CENPF, MCM4, TPX2, KIF20A, ASPM, MELK, and NEK2) were identified through network analysis. Among these, MCM4 showed strong upregulation in LUAD and was significantly associated with poor overall survival. Notably, MCM4 expression also correlated with post-progression survival and markers of invasiveness. Immunohistochemistry and transcriptomic analyses confirmed MCM4 overexpression at both mRNA and protein levels. Additionally, MCM4 expression was positively correlated with various matrix metalloproteinases, supporting its role in promoting tumor invasiveness. Conclusions: MCM4 is a novel potential biomarker for LUAD metastasis and prognosis. Its consistent upregulation, association with metastatic markers, and clinical significance suggest it may serve as a candidate target for diagnostic use or therapeutic intervention in advanced LUAD. Full article
(This article belongs to the Section Pathology and Molecular Diagnostics)
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17 pages, 2536 KiB  
Article
Drought-Induced Zinc Finger Transcription Factor OsDi19-3 Positively Regulates Drought Stress Acclimatization in Rice (Oryza sativa L.)
by Yanjie Li, Tianjiao Mu, Tianying Ren and Pan Li
Plants 2025, 14(10), 1560; https://doi.org/10.3390/plants14101560 - 21 May 2025
Viewed by 462
Abstract
The plant Di19 (drought-induced 19) protein belongs to zinc finger transcription factors, which play crucial roles in drought stress acclimatization. OsDi19-3, a drought-induced transcription factor in rice, has not been fully characterized for its biological role in stress acclimatization. In this study, transgenic [...] Read more.
The plant Di19 (drought-induced 19) protein belongs to zinc finger transcription factors, which play crucial roles in drought stress acclimatization. OsDi19-3, a drought-induced transcription factor in rice, has not been fully characterized for its biological role in stress acclimatization. In this study, transgenic rice overexpressing OsDi19-3 was generated. Water deprivation experiments showed that transgenic plants exhibited higher drought tolerance than wild-type (WT) plants, indicating that OsDi19-3 positively regulates drought stress acclimatization. Consistent with this, stomata in overexpression lines closed more significantly than those in WT under drought stress. To explore the molecular mechanism, yeast two-hybrid and bimolecular fluorescence complementation (BiFC) experiments identified two interacting proteins of OsDi19-3: OsCAMK1 and OsNEK6. Notably, these two proteins also interacted with each other. A transcriptome analysis of OsDi19-3 transgenic plants revealed 224 upregulated and 167 downregulated genes (log2(OE/WT) > 1, p-value < 0.05), including multiple stress-responsive genes. Furthermore, a ChIP-PCR analysis confirmed that OsDi19-3 directly binds to three target genes. This study provides insights into the role of OsDi19-3 in drought acclimatization and its regulatory network in rice. Full article
(This article belongs to the Special Issue Physiological and Molecular Responses for Stress Tolerance in Rice)
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17 pages, 1321 KiB  
Review
The Molecular Intersection of NEK1, C21ORF2, Cyclin F, and VCP in ALS Pathogenesis
by Yasuaki Watanabe, Tadashi Nakagawa, Makiko Nakagawa and Keiko Nakayama
Genes 2025, 16(4), 407; https://doi.org/10.3390/genes16040407 - 30 Mar 2025
Viewed by 1189
Abstract
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the progressive degeneration of motor neurons, leading to muscle weakness, paralysis, and death. Although significant progress has been made in understanding ALS, its molecular mechanisms remain complex and multifactorial. This review explores [...] Read more.
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the progressive degeneration of motor neurons, leading to muscle weakness, paralysis, and death. Although significant progress has been made in understanding ALS, its molecular mechanisms remain complex and multifactorial. This review explores the potential convergent mechanisms underlying ALS pathogenesis, focusing on the roles of key proteins including NEK1, C21ORF2, cyclin F, VCP, and TDP-43. Recent studies suggest that mutations in C21ORF2 lead to the stabilization of NEK1, while cyclin F mutations activate VCP, resulting in TDP-43 aggregation. TDP-43 aggregation, a hallmark of ALS, impairs RNA processing and protein transport, both of which are essential for neuronal function. Furthermore, TDP-43 has emerged as a key player in DNA damage repair, translocating to DNA damage sites and recruiting repair proteins. Given that NEK1, VCP, and cyclin F are also involved in DNA repair, this review examines how these proteins may intersect to disrupt DNA damage repair mechanisms, contributing to ALS progression. Impaired DNA repair and protein homeostasis are suggested to be central downstream mechanisms in ALS pathogenesis. Ultimately, understanding the interplay between these pathways could offer novel insights into ALS and provide potential therapeutic targets. This review aims to highlight the emerging connections between protein aggregation, DNA damage repair, and cellular dysfunction in ALS, fostering a deeper understanding of its molecular basis and potential avenues for intervention. Full article
(This article belongs to the Special Issue Molecular Genetics and Pathogenesis of Motor Neuron Disease)
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17 pages, 2006 KiB  
Review
Targeting NEK Kinases in Gastrointestinal Cancers: Insights into Gene Expression, Function, and Inhibitors
by Lei Chen, Heng Lu, Farah Ballout, Wael El-Rifai, Zheng Chen, Ravindran Caspa Gokulan, Oliver Gene McDonald and Dunfa Peng
Int. J. Mol. Sci. 2025, 26(5), 1992; https://doi.org/10.3390/ijms26051992 - 25 Feb 2025
Cited by 1 | Viewed by 1325
Abstract
Gastrointestinal (GI) cancers, which mainly include malignancies of the esophagus, stomach, intestine, pancreas, liver, gallbladder, and bile duct, pose a significant global health burden. Unfortunately, the prognosis for most GI cancers remains poor, particularly in advanced stages. Current treatment options, including targeted and [...] Read more.
Gastrointestinal (GI) cancers, which mainly include malignancies of the esophagus, stomach, intestine, pancreas, liver, gallbladder, and bile duct, pose a significant global health burden. Unfortunately, the prognosis for most GI cancers remains poor, particularly in advanced stages. Current treatment options, including targeted and immunotherapies, are less effective compared to those for other cancer types, highlighting an urgent need for novel molecular targets. NEK (NIMA related kinase) kinases are a group of serine/threonine kinases (NEK1-NEK11) that play a role in regulating cell cycle, mitosis, and various physiological processes. Recent studies suggest that several NEK members are overexpressed in human cancers, including gastrointestinal (GI) cancers, which can contribute to tumor progression and drug resistance. Among these, NEK2 stands out for its consistent overexpression in all types of GI cancer. Targeting NEK2 with specific inhibitors has shown promising results in preclinical studies, particularly for gastric and pancreatic cancers. The development and clinical evaluation of NEK2 inhibitors in human cancers have emerged as a promising therapeutic strategy. Specifically, an NEK2 inhibitor, T-1101 tosylate, is currently undergoing clinical trials. This review will focus on the gene expression and functional roles of NEKs in GI cancers, as well as the progress in developing NEK inhibitors. Full article
(This article belongs to the Special Issue Molecular Targets in Gastrointestinal Diseases)
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21 pages, 9488 KiB  
Article
Identification of Immune Infiltration-Associated CC Motif Chemokine Ligands as Biomarkers and Targets for Colorectal Cancer Prevention and Immunotherapy
by Minghao Liu, Teng Wang and Mingyang Li
Int. J. Mol. Sci. 2025, 26(2), 625; https://doi.org/10.3390/ijms26020625 - 13 Jan 2025
Viewed by 1326
Abstract
Colorectal cancer (CRC) is the third most common cancer globally, with limited effective biomarkers and sensitive therapeutic targets. An increasing number of studies have highlighted the critical role of tumor microenvironment (TME) imbalances, particularly immune escape due to impaired chemokine-mediated trafficking, in tumorigenesis [...] Read more.
Colorectal cancer (CRC) is the third most common cancer globally, with limited effective biomarkers and sensitive therapeutic targets. An increasing number of studies have highlighted the critical role of tumor microenvironment (TME) imbalances, particularly immune escape due to impaired chemokine-mediated trafficking, in tumorigenesis and progression. Notably, CC chemokines (CCLs) have been shown to either promote or inhibit angiogenesis, metastasis, and immune responses in tumors, thereby influencing cancer development and patient outcomes. However, the diagnostic and prognostic significance of CCLs in CRC remains unclear. In this study, multiple online tools for bioinformatics analyses were utilized. The findings revealed that the mRNA expression levels of CCL3, CCL4, and CCL26 were significantly elevated in CRC tissues compared to normal tissues, whereas CCL2, CCL5, CCL11, CCL21, and CCL28 mRNA levels were markedly downregulated. Additionally, dysregulation of CCL4, CCL5, and CCL21 was strongly associated with clinical staging, and elevated levels of CCL4, CCL11, and CCL28 were linked to significantly prolonged survival in CRC patients. Functional enrichment analysis indicated that the cellular roles of CCLs were predominantly associated with the chemokine, Wnt, and Toll-like receptor signaling pathways, as well as protein kinase activity. Furthermore, transcriptional regulation of most CCLs involved RELA and NFKB1. Key downstream targets included members of the SRC family of tyrosine kinases (HCK, LYN, and LCK), serine/threonine kinases (ATR and ATM), and others such as CSNK1G2, NEK2, and CDK2. Moreover, CCLs (CCL2, CCL3, CCL4, CCL5, CCL11, CCL21, and CCL28) exhibited strong correlations with major infiltration-related immune cells, including B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells. In conclusion, our study provides novel insights into the potential utility of CCLs as biomarkers and therapeutic targets for CRC prevention and immunotherapy. Full article
(This article belongs to the Section Molecular Informatics)
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9 pages, 431 KiB  
Commentary
Beyond the Horizon: Rethinking Prostate Cancer Treatment Through Innovation and Alternative Strategies
by Siddhant Bhoir and Arrigo De Benedetti
Cancers 2025, 17(1), 75; https://doi.org/10.3390/cancers17010075 - 29 Dec 2024
Cited by 1 | Viewed by 1582
Abstract
For nearly a century, fundamental observations that prostate cancer (PCa) cells nearly always require AR stimulation for sustained proliferation have led to a unidirectional quest to abrogate such a pathway. Similarly focused have been efforts to understand AR-driven processes in the context of [...] Read more.
For nearly a century, fundamental observations that prostate cancer (PCa) cells nearly always require AR stimulation for sustained proliferation have led to a unidirectional quest to abrogate such a pathway. Similarly focused have been efforts to understand AR-driven processes in the context of elevated expression of its target genes, and much less so on products that become overexpressed when AR signaling is suppressed. Treatment with ARSI results in an increased expression of the TLK1B splice variant via a ‘translational’ derepression driven by the compensatory mTOR activation and consequent activation of the TLK1 > NEK1 > ATR > Chk1 and NEK1 > YAP axes. In due course, this results first in a pro-survival quiescence and then adaptation to ADT and CRPC progression. This constitutes a novel liability for PCa that we have targeted for several years and novel approaches. Full article
(This article belongs to the Special Issue Insights from the Editorial Board Member)
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19 pages, 5749 KiB  
Article
NEK2 Phosphorylates RhoGDI1 to Promote Cell Proliferation, Migration and Invasion Through the Activation of RhoA and Rac1 in Colon Cancer Cells
by Jeewon Lim, Yo-Sep Hwang, Jong-Tae Kim, Hyang-Ran Yoon, Hyo-Min Park, Jahyeong Han, Taeho Kwon, Kyung-Ho Lee, Hee-Jun Cho and Hee-Gu Lee
Cells 2024, 13(24), 2072; https://doi.org/10.3390/cells13242072 - 16 Dec 2024
Cited by 1 | Viewed by 1186
Abstract
Rho guanine nucleotide dissociation inhibitor 1 (RhoGDI1) plays a critical role in regulating the activity of Rho guanosine triphosphatases (GTPases). Phosphorylation of RhoGDI1 dynamically modulates the activation of Rho GTPases, influencing cell proliferation and migration. This study explored the involvement of Never In [...] Read more.
Rho guanine nucleotide dissociation inhibitor 1 (RhoGDI1) plays a critical role in regulating the activity of Rho guanosine triphosphatases (GTPases). Phosphorylation of RhoGDI1 dynamically modulates the activation of Rho GTPases, influencing cell proliferation and migration. This study explored the involvement of Never In Mitosis A (NIMA)-related serine/threonine protein kinase 2 (NEK2) in phosphorylating RhoGDI1 and its implications in cancer cell behavior associated with tumor progression. We employed GST pull-down assays and immunoprecipitation to investigate the interaction between NEK2 and RhoGDI1. Truncation fragments identified the region of RhoGDI1 responsible for binding with NEK2. Phosphorylation assays determined the site of NEK2-mediated phosphorylation on RhoGDI1. Functional assays were conducted using overexpression of the RhoGDI1 substitution mutant to assess their impact on cancer cell behavior. NEK2 directly bound to RhoGDI1 and phosphorylated it at Ser174. This phosphorylation event facilitated cancer cell proliferation and motility by activating RhoA and Rac1. The RhoGDI1 aa 112–134 region was critical for the binding to NEK2. Disruption of the NEK2–RhoGDI1 interaction through overexpression of a RhoGDI1 truncated fragment (aa 112–134) led to diminished RhoGDI1 phosphorylation and RhoA/Rac1 activation induced by NEK2, resulting in reduced cancer cell proliferation and migration. Moreover, in vivo studies showed reduced tumor growth and lung metastasis when the NEK2–RhoGDI1 interaction was disrupted. This study indicates that NEK2 promotes the metastatic behaviors of cancer cells by activating RhoA and Rac1 by phosphorylating RhoGDI1. Full article
(This article belongs to the Collection Rho GTPases in Health and Disease)
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23 pages, 4959 KiB  
Article
Microtubule Association of EML4–ALK V3 Is Key for the Elongated Cell Morphology and Enhanced Migration Observed in V3 Cells
by Savvas Papageorgiou, Sarah L. Pashley, Laura O’Regan, Kees R. Straatman and Andrew M. Fry
Cells 2024, 13(23), 1954; https://doi.org/10.3390/cells13231954 - 25 Nov 2024
Viewed by 1325
Abstract
The EML4–ALK oncogene drives tumour progression in approximately 5% of cases of non-small-cell lung cancers. At least 15 EML4–ALK variants have been identified, which elicit differential responses to conventional ALK inhibitors. Unfortunately, most, if not all, patients eventually acquire resistance to these inhibitors [...] Read more.
The EML4–ALK oncogene drives tumour progression in approximately 5% of cases of non-small-cell lung cancers. At least 15 EML4–ALK variants have been identified, which elicit differential responses to conventional ALK inhibitors. Unfortunately, most, if not all, patients eventually acquire resistance to these inhibitors and succumb to the disease, which warrants the need for alternative targets to be identified. The most aggressive variant, EML4–ALK variant 3 (V3), assembles into a complex on interphase microtubules together with the NEK9 and NEK7 kinases, which leads to the downstream phosphorylation of NEK7 substrates. Overall, this promotes an elongated cell morphology and an enhanced migratory phenotype, which likely contributes to the increased metastasis often seen in V3 patients. Here, using two separate approaches to displace V3 from microtubules and a variety of in vitro assays, we show that microtubule association of EML4–ALK V3 is required for both V3 phenotypes, as removal of the oncogenic fusion protein from microtubules led to the dissociation of the V3–NEK9–NEK7 complex and the reversal of both phenotypic changes. Overall, we propose that targeting the interaction between EML4–ALK V3 and microtubules might offer a novel therapeutic option, independent of ALK activity, for V3+ NSCLC patients with acquired resistance to ALK inhibitors. Full article
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15 pages, 38656 KiB  
Article
A Numerical Study of Flow Past a Wall-Mounted Dolphin Dorsal Fin at Low Reynolds Numbers
by Zhonglu Lin, Ankang Gao and Yu Zhang
Biomimetics 2024, 9(11), 682; https://doi.org/10.3390/biomimetics9110682 - 7 Nov 2024
Viewed by 1398
Abstract
Dolphin swimming has been a captivating subject, yet the dorsal fin’s hydrodynamics remain underexplored. In this study, we conducted three-dimensional simulations of flow around a wall-mounted dolphin dorsal fin derived from a real dolphin scan. The NEK5000 (spectral element method) was employed with [...] Read more.
Dolphin swimming has been a captivating subject, yet the dorsal fin’s hydrodynamics remain underexplored. In this study, we conducted three-dimensional simulations of flow around a wall-mounted dolphin dorsal fin derived from a real dolphin scan. The NEK5000 (spectral element method) was employed with a second-order hex20 mesh to ensure high simulation accuracy and efficiency. A total of 13 cases were simulated, covering angles of attack (AoAs) ranging from 0° to 60° and Reynolds numbers (Re) between 691 and 2000. Our results show that both drag and lift increase significantly with the AoA. Almost no vortex was observed at AoA=0°, whereas complex vortex structures emerged for AoA30°, including half-horseshoe, hairpin, arch, and wake vortices. This study offers insights that can inform the design of next-generation underwater robots, heat exchangers, and submarine sails. Full article
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20 pages, 6452 KiB  
Article
Dynamic Mitotic Localization of the Centrosomal Kinases CDK1, Plk, AurK, and Nek2 in Dictyostelium amoebae
by Stefan Krüger, Nathalie Pfaff, Ralph Gräf and Irene Meyer
Cells 2024, 13(18), 1513; https://doi.org/10.3390/cells13181513 - 10 Sep 2024
Cited by 1 | Viewed by 1319
Abstract
The centrosome of the amoebozoan model Dictyostelium discoideum provides the best-established model for an acentriolar centrosome outside the Opisthokonta. Dictyostelium exhibits an unusual centrosome cycle, in which duplication is initiated only at the G2/M transition and occurs entirely during the M phase. [...] Read more.
The centrosome of the amoebozoan model Dictyostelium discoideum provides the best-established model for an acentriolar centrosome outside the Opisthokonta. Dictyostelium exhibits an unusual centrosome cycle, in which duplication is initiated only at the G2/M transition and occurs entirely during the M phase. Little is known about the role of conserved centrosomal kinases in this process. Therefore, we have generated knock-in strains for Aurora (AurK), CDK1, cyclin B, Nek2, and Plk, replacing the endogenous genes with constructs expressing the respective green fluorescent Neon fusion proteins, driven by the endogenous promoters, and studied their behavior in living cells. Our results show that CDK1 and cyclin B arrive at the centrosome first, already during G2, followed by Plk, Nek2, and AurK. Furthermore, CDK1/cyclin B and AurK were dynamically localized at kinetochores, and AurK in addition at nucleoli. The putative roles of all four kinases in centrosome duplication, mitosis, cytokinesis, and nucleolar dynamics are discussed. Full article
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16 pages, 3408 KiB  
Article
TLK1>Nek1 Axis Promotes Nuclear Retention and Activation of YAP with Implications for Castration-Resistant Prostate Cancer
by Damilola Olatunde and Arrigo De Benedetti
Cancers 2024, 16(16), 2918; https://doi.org/10.3390/cancers16162918 - 22 Aug 2024
Cited by 3 | Viewed by 1900
Abstract
Despite some advances in controlling the progression of prostate cancer (PCa) that is refractory to the use of ADT/ARSI, most patients eventually succumb to the disease, and there is a pressing need to understand the mechanisms that lead to the development of CRPC. [...] Read more.
Despite some advances in controlling the progression of prostate cancer (PCa) that is refractory to the use of ADT/ARSI, most patients eventually succumb to the disease, and there is a pressing need to understand the mechanisms that lead to the development of CRPC. A common mechanism is the ability to integrate AR signals from vanishing levels of testosterone, with the frequent participation of YAP as a co-activator, and pointing to the deregulation of the Hippo pathway as a major determinant. We have recently shown that YAP is post-transcriptionally activated via the TLK1>NEK1 axis by stabilizing phosphorylation at Y407. We are now solidifying this work by showing the following: (1) The phosphorylation of Y407 is critical for YAP retention/partition in the nuclei, and J54 (TLK1i) reverses this along with YAP-Y407 dephosphorylation. (2) The enhanced degradation of (cytoplasmic) YAP is increased by J54 counteracting its Enzalutamide-induced accumulation. (3) The basis for all these effects, including YAP nuclear retention, can be explained by the stronger association of pYAP-Y407 with its transcriptional co-activators, AR and TEAD1. (4) We demonstrate that ChIP for GFP-YAP-wt, but hardly for the GFP-YAP-Y407F mutant, at the promoters of typical ARE- and TEAD1-driven genes is readily detected but becomes displaced after treatment with J54. (5) While xenografts of LNCaP cells show rapid regression following treatment with ARSI+J54, in the VCaP model, driven by the TMPRSS2-ERG oncogenic translocation, tumors initially respond well to the combination but subsequently recur, despite the continuous suppression of pNek1-T141 and pYAP-Y407. This suggests an alternative parallel pathway for CRPC progression for VCaP tumors in the long term, which may be separate from the observed ENZ-driven YAP deregulation, although clearly some YAP gene targets like PD-L1, that are found to accumulate following prolonged ENZ treatment, are still suppressed by the concomitant addition of J54. Full article
(This article belongs to the Section Cancer Therapy)
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8 pages, 1165 KiB  
Communication
Protective Activities of Growth Hormone-Releasing Hormone Antagonists against Toxin-Induced Endothelial Injury
by Saikat Fakir and Nektarios Barabutis
Endocrines 2024, 5(1), 116-123; https://doi.org/10.3390/endocrines5010008 - 18 Mar 2024
Cited by 12 | Viewed by 2231
Abstract
GHRH regulates the secretion of GH from the anterior pituitary gland, previously associated with cancer progression and inflammation. An emerging body of evidence suggests that GHRHAnt support endothelial barrier function, but the mechanisms mediating these events are not completely understood. In the present [...] Read more.
GHRH regulates the secretion of GH from the anterior pituitary gland, previously associated with cancer progression and inflammation. An emerging body of evidence suggests that GHRHAnt support endothelial barrier function, but the mechanisms mediating these events are not completely understood. In the present study, it is demonstrated that the GHRHAnt JV-1-36 counteracts barrier dysfunction due to LPS or LTA treatment in HUVECs, utilizing the Dextran–FITC assay. Moreover, it is shown in BPAECs that these bacterial toxins increase ROS generation, and that this effect is counteracted by JV-1-36, which reinstates the redox balance. The possible involvement of NEK2 in the beneficial activities of GHRHAnt in IFN-γ- and LPS-triggered hyperpermeability was also assessed, since that kinase is involved in inflammatory responses. NEK2 was increased in the inflamed cells, and JV-1-36 counteracted those endothelial events. Our data support the beneficial effects of GHRHAnt in toxin-induced endothelial injury. Full article
(This article belongs to the Special Issue Feature Papers in Endocrines: 2024)
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36 pages, 4065 KiB  
Review
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 5 | Viewed by 3750
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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19 pages, 5021 KiB  
Article
Regulation of myo-miR-24-3p on the Myogenesis and Fiber Type Transformation of Skeletal Muscle
by Danyang Fan, Yilong Yao, Yanwen Liu, Chao Yan, Fanqinyu Li, Shilong Wang, Mei Yu, Bingkun Xie and Zhonglin Tang
Genes 2024, 15(3), 269; https://doi.org/10.3390/genes15030269 - 21 Feb 2024
Cited by 5 | Viewed by 2620
Abstract
Skeletal muscle plays critical roles in providing a protein source and contributing to meat production. It is well known that microRNAs (miRNAs) exert important effects on various biological processes in muscle, including cell fate determination, muscle fiber morphology, and structure development. However, the [...] Read more.
Skeletal muscle plays critical roles in providing a protein source and contributing to meat production. It is well known that microRNAs (miRNAs) exert important effects on various biological processes in muscle, including cell fate determination, muscle fiber morphology, and structure development. However, the role of miRNA in skeletal muscle development remains incompletely understood. In this study, we observed a critical miRNA, miR-24-3p, which exhibited higher expression levels in Tongcheng (obese-type) pigs compared to Landrace (lean-type) pigs. Furthermore, we found that miR-24-3p was highly expressed in the dorsal muscle of pigs and the quadriceps muscle of mice. Functionally, miR-24-3p was found to inhibit proliferation and promote differentiation in muscle cells. Additionally, miR-24-3p was shown to facilitate the conversion of slow muscle fibers to fast muscle fibers and influence the expression of GLUT4, a glucose transporter. Moreover, in a mouse model of skeletal muscle injury, we demonstrated that overexpression of miR-24-3p promoted rapid myogenesis and contributed to skeletal muscle regeneration. Furthermore, miR-24-3p was found to regulate the expression of target genes, including Nek4, Pim1, Nlk, Pskh1, and Mapk14. Collectively, our findings provide evidence that miR-24-3p plays a regulatory role in myogenesis and fiber type conversion. These findings contribute to our understanding of human muscle health and have implications for improving meat production traits in livestock. Full article
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