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Results for “Polo-Like Kinase 1”

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6 recordsLinked to original sources
PubMed2025

The Role of Polo-Like Kinase 1 (PLK1) O-GlcNAcylation in Mitosis.

Polo-like kinase 1 (PLK1) is a crucial mitotic kinase that is implicated in various aspects of cell cycle. Many post-translational modifications have been identified on PLK1 to regulate its activation, stability, and localization. PLK1 has been shown previously to colocalize with the O-linked β-N-acetylglucosamine (O-GlcNAc) transferase (OGT), and OGT regulates PLK1 stability. In our recent work, we show that PLK1 is O-GlcNAcylated by click chemistry. Using stepped collisional energy/higher energy collision dissociation mass spectrometry, we mapped the PLK1 O-GlcNAc site to be T291. We further utilized fluorescent activated cell sorting and time-lapse microscopy to assess the mitotic defects of PLK1 O-GlcNAc mutants. In vivo studies in mouse xenograft demonstrated that it promoted uterine cancer tumorigenesis. In this chapter, we delineate the methodologies we used in studying PLK1 O-GlcNAcylation, including click chemistry, stepped collisional energy/higher energy collision dissociation mass spectrometry, fluorescent activated cell sorting, time-lapse microscopy, and mouse xenograft assays.

Polo-Like Kinase 1↗
PubMed2026

Selective Macrocyclic WEE1 Kinase Inhibitors with Strong Efficacy against Patient-Derived Colorectal Cancer Organoids.

Macrocyclization can enhance the selectivity of acyclic compounds toward structurally similar biological targets such as kinases. WEE1 regulates cellular homeostasis and is a promising target in oncology. The clinical candidate AZD1775 (1) failed to progress past Phase II trials because of patient tolerability issues, likely due to off-target inhibition of polo-like kinase 1 (PLK1). Herein, a computer-aided drug design approach was conducted to develop a macrocycle based on the 1-WEE1 X-ray cocrystal structure. Significantly enhanced WEE1 inhibitory selectivity over PLK1 was determined for leading macrocycle 2, which also demonstrated broader kinome-wide selectivity. Patient-derived organoids from colorectal cancer (CRC) peritoneal and liver metastases, treated with 2, demonstrated comparably strong or enhanced anticancer efficacy compared to that of 1. Against patient-matched normal colon vs primary CRC organoids, 2 potently and selectively treated CRC, as well as enhanced DNA damage compared to 1. Finally, the X-ray cocrystal structure of 2 bound to WEE1 validated its computationally predicted bioactive binding mode.

Humans↗
PubMed2026

GSK3β and Plk1 sequentially phosphorylate ATP-citrate lyase to promote homologous recombination.

Accurate repair of DNA double-strand breaks (DSBs) by homologous recombination (HR) is essential for genome stability. Nuclear production of acetyl-coenzyme A (acetyl-CoA) by ATP-citrate lyase (ACLY) promotes HR, yet how ACLY is regulated during the DNA damage response (DDR) remains unclear. Here, we identify a phosphorylation-dependent signaling axis in which glycogen synthase kinase 3β (GSK3β) and Polo-like kinase 1 (Plk1) act sequentially on ACLY to facilitate HR-mediated repair of DSBs induced by ionizing radiation. Following AKT-dependent phosphorylation of ACLY at Ser455, GSK3β phosphorylates ACLY at Thr447, generating a docking site for Plk1, which in turn phosphorylates ACLY at Ser442. This phosphorylation cascade, enhanced by radiation, sustains histone acetylation, supports the accumulation of BRCA1 and RAD51 at DSBs, and confers cellular resistance to poly(ADP-ribose) polymerase (PARP) inhibition. Together, our findings define an AKT-GSK3β-Plk1-ACLY signaling module that links the DDR to nuclear metabolism, revealing a critical mechanism by which kinase signaling facilitates acetyl-CoA-dependent chromatin remodeling to preserve genome integrity.

Protein Serine-Threonine Kinases↗
PubMed2026

Determinants of protein phosphatase 1β substrate specificity for MyPhoNE motif-containing proteins.

Phosphoprotein phosphatase 1 (PP1) forms holoenzymes composed of a catalytic subunit (PP1c) and one or two of over 200 regulatory subunits (PP1Rs). Humans express four conserved PP1c isoforms: PP1cα, PP1cβ/δ, and splice variants PP1cγ1 and PP1cγ2. To systematically characterize PP1c isoform-specific interactions, we employed mass spectrometry to identify PP1cα, PP1cβ, and PP1cγ interacting proteins, determine their isoform specificity, and assess and quantify their abundance within the PP1 holoenzyme pool. Our data show that PP1c forms hundreds of dimeric and trimeric holoenzymes, but the 10 most abundant PP1Rs make up 74% of PP1 holoenzymes, and they are highly uniform among PP1c isoforms. A key exception is myosin phosphatase N-terminal element (MyPhoNE)-containing PP1Rs, which form abundant holoenzyme complexes exclusively with PP1cβ. To define the determinants of MYPT1-PP1cβ specificity, we systematically assessed the contributions of MYPT1-PP1cβ interactions. First, we generated PP1cβ-PP1cγ chimeras and PP1cβ Tyr 305/Tyr307 point mutations to test the contribution of the PP1 C-terminal residues, and secondly, we used PP1cβ Thr197Gln (T197Q) mutation to test the effect of the MYPT1:MyPhoNE-specific interaction. Using genome editing, we demonstrate that PP1cβ T197Q-expressing cells exhibit altered PP1 holoenzyme composition and phosphorylation signaling, including increased phosphorylation of the Polo-like kinase 1 (Plk1) activation loop. Our studies further the understanding of the PP1c isoform-specific preference and demonstrate how a single amino acid change can alter PP1 holoenzyme composition and phosphorylation signaling, potentially explaining how recently discovered PP1cβ clinical variants impact PP1 biology.

MyPhoNE motif↗
PubMed2026

PLK1/FOXM1-associated tumor-cell state and macrophage-related immune features in endometrial cancer.

BACKGROUND: Polo-like kinase 1 (PLK1) and forkhead box M1 (FOXM1) have been widely studied in various cancers; however, their expression characteristics in endometrial cancer (EC) and their potential association with tumor microenvironment remodeling remain insufficiently characterized. METHODS: This study integrated The Cancer Genome Atlas uterine corpus endometrial carcinoma cohort, Gene Expression Omnibus, pan-cancer transcriptomic data, Human Protein Atlas/Clinical Proteomic Tumor Analysis Consortium, and local immunohistochemistry data to evaluate PLK1 expression and clinicopathological relevance across transcriptomic, proteomic, and histopathological data. Differential expression, survival, gene-set enrichment, transcription-factor enrichment, and immune-infiltration analyses characterized PLK1-associated features. In vitro experiments combined EC cell lines AN3CA and HEC-1A with co-immunoprecipitation, Western blotting, Transwell assays, and a THP-1 conditioned-medium model. Drug-response prediction and structure-based analysis prioritized candidate therapeutic hypotheses. RESULTS: PLK1 was consistently upregulated at both mRNA and protein levels in EC and was associated with higher tumor grade and International Federation of Gynecology and Obstetrics (FIGO) stage. In survival analysis, higher PLK1 expression was associated with poorer overall survival in univariable models but not after adjustment for age, tumor grade, and FIGO stage. Functional enrichment analysis showed that PLK1-associated genes were mainly involved in cell-cycle and mitotic processes. FOXM1 was identified as a potential candidate component of the PLK1-associated transcriptional program and was positively correlated with PLK1 expression and cell-cycle-related features. In vitro experiments supported an interaction between PLK1 and FOXM1 and suggested that FOXM1 Thr600 phosphorylation-related alterations were associated with migration and invasion phenotypes. Furthermore, the PLK1/FOXM1-associated tumor-cell state was linked to macrophage-related immune features and changes in the M2-like marker profile of THP-1-derived macrophage-like cells. Drug response analyses suggested differential predicted sensitivity patterns in PLK1-high tumors, providing candidate therapeutic hypotheses for further validation. CONCLUSION: The PLK1/FOXM1-associated tumor-cell state may represent a distinct molecular feature associated with proliferative activity, invasive phenotypes, and macrophage-related immune features in EC. This study provides preliminary evidence supporting the biological relevance of this molecular feature and highlights potential therapeutic directions for future investigation.

FoxM1↗
PubMed2025

An anti-androgen resistance-related gene signature acts as a prognostic marker and increases enzalutamide efficacy via PLK1 inhibition in prostate cancer.

BACKGROUND: Anti-androgen resistance remains a major clinical challenge in the treatment of prostate cancer (PCa), leading to disease progression and treatment failure. Despite extensive research on resistance mechanisms, a reliable prognostic model for predicting patient outcomes and guiding therapeutic strategies is still lacking. This study aimed to develop a novel gene signature related to anti-androgen resistance and evaluate its prognostic and therapeutic implications. METHODS: Anti-androgen resistance-related differentially expressed genes (ARRDEGs) were identified through transcriptomic analysis of enzalutamide- and dual enzalutamide abiraterone-resistant PCa cell lines from the GEO database. Functional enrichment analysis was performed to determine the biological roles of these genes. A prognostic gene signature was developed using univariate Cox regression, LASSO, and multivariate Cox regression models. The model was validated in independent PCa cohorts from The Cancer Genome Atlas (TCGA). Additionally, we assessed the correlation between the signature, immune infiltration, immune checkpoint expression, and drug sensitivity. The efficacy of PLK1 inhibition combined with enzalutamide was further explored using in vitro and in vivo experiments. RESULTS: We identified 304 ARRDEGs, from which three key genes (LMNB1, SSPO, and PLK1) were selected to construct a prognostic signature. This gene signature effectively stratified PCa patients into high- and low-risk groups, with the high-risk group exhibiting shorter recurrence-free survival and distinct immune characteristics. High-risk patients demonstrated elevated immune checkpoint expression (B7H3, CTLA-4, B7-1, and TIGIT), increased M2 macrophage infiltration, and enhanced sensitivity to chemotherapy and targeted therapy. Mechanistically, PLK1 inhibition potentiated the antitumor effect of enzalutamide by downregulating SLC7A11 and inducing ferroptosis, providing a potential therapeutic strategy to overcome anti-androgen resistance. CONCLUSION: We established a novel ARRDEGs-based prognostic signature that predicts PCa progression and response to chemotherapy and targeted therapy. The integration of this signature with immune profiling and drug sensitivity analysis provides a valuable tool for precision oncology in PCa. Our findings highlight the potential of PLK1 inhibition as a therapeutic strategy to enhance enzalutamide efficacy and overcome resistance.

Humans↗