Role of PLK1 in epithelial-mesenchymal transition in human melanoma
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE237385 | GEO | 2024/01/01
REPOSITORIES: GEO
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Project description:Melanoma is one of the most serious forms of skin cancer, and its increasing incidence coupled with non-lasting therapeutic options for metastatic disease highlight the need for additional novel approaches for its management. In this study, we determined the potential interactions between polo-like kinase 1 (PLK1, a serine/threonine kinase involved in mitotic regulation) and NOTCH1 (a type I transmembrane protein deciding cell fate during development) in melanoma. Employing an in-house human melanoma tissue microarray (TMA) containing multiple cases of melanomas and benign nevi, coupled with high-throughput, multispectral quantitative fluorescence imaging analysis, we found a positive correlation between PLK1 and NOTCH1 in melanoma. Further, TCGA database analysis of melanoma patients showed an association of higher mRNA levels of PLK1 and NOTCH1 with poor overall as well as disease-free survival. Next, utilizing small-molecule inhibitors of PLK1 and NOTCH (BI 6727 and MK-0752, respectively), we found a synergistic anti-proliferative response of combined treatment in multiple human melanoma cells. To determine the molecular targets of the overall and synergistic responses of combined PLK1-NOTCH inhibition, we conducted RNA-sequencing analysis employing a unique regression model with interaction terms. We identified the modulations of several key genes relevant to melanoma progression/metastasis, including MAPK, PI3K, and RAS, as well as some new genes such as Apobec3G, BTK and FCER1G which have not been well-studied in melanoma. In conclusion, our study demonstrated a synergistic anti-proliferative response of a concomitant targeting of PLK1 and NOTCH in melanoma, unravelling a potential novel therapeutic approach for detailed preclinical/clinical evaluation.
2020-10-07 | GSE159095 | GEO
Project description:Metastasis of Lung adenocarcinoma (LUAD) is a major cause of death in patients. Aryl hydrocarbon receptor (AHR) is an important transcription factor involved in the initiation and progression of lung cancer. Polo-like kinase 1 (PLK1), a serine/threonine kinase, is an oncogene that promotes the malignancy of multiple cancer types. Nonetheless, the interaction between these two factors and significance in lung cancer remains to be determined. Here, we demonstrate that PLK1 phosphorylates AHR at S489 in LUAD, which leads to epithelial-mesenchymal transition (EMT) and metastatic events. RNA-seq analyses show that type 2 deiodinase (DIO2) is responsible for EMT and enhanced metastatic potential. DIO2 converts tetraiodothyronine (T4) to triiodothyronine (T3), which then activates thyroid hormone signaling. In vitro and in vivo experiments demonstrate that treatment with T3 or T4 promotes the metastasis of LUAD, whereas depletion of DIO2 or deiodinase inhibitor disrupts this property. Taken together, our results identify the phosphorylation of AHR by PLK1 as a mechanism leading to the progression of LUAD and provide possible therapeutic interventions for this event.
2023-10-22 | GSE241973 | GEO
Project description:Although 3-Phosphoinositide-dependent protein kinase-1 (PDK1) has been predominately linked to PI3K-AKT pathway, it may also evoke additional signaling outputs to promote tumorigenesis. Here we report that PDK1 directly induces phosphorylation of Polo-like kinase 1 (PLK1), which in turn induces Myc phosphorylation and protein accumulation. We show that PDK1-PLK1-Myc signaling is critical for cancer cell growth and survival and small molecule inhibition of PDK1/PLK1 provides an effective approach for therapeutic targeting Myc-dependency. Intriguingly, PDK1-PLK1-Myc signaling induces an embryonic stem cell-like gene signature associated with aggressive tumor behaviors and is a robust signaling axis driving cancer stem cell (CSC) self renewal. Finally, we show that PLK1 inhibitor synergizes with mTOR inhibitor to induce synergistic anti-tumor effect in colorectal cancer by antagonizing a compensatory Myc induction. These findings identify a novel pathway in human cancer and CSC activation and provide a therapeutic strategy for targeting Myc-associated tumorigenesis and therapeutic resistance. Gene expression profiling of Human Embryonic Kidney Cells (HEK-TERV) under different conditions: PMN, PDK1, MYC and E545K
2013-07-31 | E-GEOD-30669 | biostudies-arrayexpress
Project description:Polo-like kinase 1 (PLK1) is a serine/threonine kinase required for mitosis and cytokinesis. As cancer cells are often hypersensitive to partial PLK1 inactivation, chemical inhibitors of PLK1 have been developed and tested in clinical trials. However, these molecules alone were not completely effective. PLK1 promotes numerous molecular and cellular events in the cell division cycle. To date, it is unclear which of these events most crucially depend on PLK1 activity. We used a CRISPR-based genome-wide screening strategy to identify genes whose inactivation enhances cell proliferation defects upon partial chemical inhibition of PLK1. Genes identified encode proteins that are functionally linked to PLK1 in multiple ways. Among them, factors that promote centromere and kinetochore function were clearly enriched. In particular, inactivation of the kinesin KIF18A or SKA1 in PLK1-compromised cells results in mitotic defects, activation of the spindle assembly checkpoint and nuclear reassembly defects. Our results suggest that functions of PLK1 at kinetochores are most sensitive to its inhibition, and point at KIF18A as a possible target for combinatorial therapies using existing PLK1 inhibitors.
2023-10-02 | GSE228155 | GEO
Project description:Polo-like kinase 1 (Plk1) is an important protein kinase for checkpoint recovery and adaptation in response to DNA damage and replication stress. However, although Plk1 is present in S phase, little is known about its localization and function during unperturbed DNA replication. Here used recombinant XRif1 C-terminal domain and recombinant XPlk1 in an in vitro phosphorylation assay followed by LC/MS/MS to identify which residues are phosphorylated by Plk1 on Rif1 CTD.
2021-08-26 | PXD022410 | Pride
Project description:Fibrolamellar carcinoma (FLC), a rare and fatal liver cancer lacking effective drug therapy, is driven by the DNAJ-PKAc fusion oncoprotein. However, the underlying mechanism of DNAJ-PKAc's role in FLC tumor growth remains enigmatic. Employing an unbiased systems-based approach, we uncovered a new role of DNAJ-PKAc oncoprotein in FLC and identified downstream kinases involved in this process. Functional screening, coupled with computational analysis, highlighted Polo-like kinase 1 (PLK1) as vital for FLC cell viability. Genetic and pharmacological PLK1 inhibition significantly reduced FLC cell growth, inducing apoptosis. Further studies showed DNAJ-PKAc's centrosomal presence and direct interaction with PLK1, revealing a novel mechanism that promotes PLK1 activation and mitotic progression. Clinical-grade PLK1 inhibitors effectively suppressed FLC tumor growth across multiple preclinical models, including patient-derived xenograft and an orthotopic model of FLC, suggesting promising therapeutic avenues. Our findings underscore the role of DNAJ-PKAc in rewiring signaling networks and highlight valuable clinical implications for PLK1-targeted therapies for FLC.
2023-12-19 | GSE250059 | GEO
Project description:Although 3-Phosphoinositide-dependent protein kinase-1 (PDK1) has been predominately linked to PI3K-AKT pathway, it may also evoke additional signaling outputs to promote tumorigenesis. Here we report that PDK1 directly induces phosphorylation of Polo-like kinase 1 (PLK1), which in turn induces Myc phosphorylation and protein accumulation. We show that PDK1-PLK1-Myc signaling is critical for cancer cell growth and survival and small molecule inhibition of PDK1/PLK1 provides an effective approach for therapeutic targeting Myc-dependency. Intriguingly, PDK1-PLK1-Myc signaling induces an embryonic stem cell-like gene signature associated with aggressive tumor behaviors and is a robust signaling axis driving cancer stem cell (CSC) self renewal. Finally, we show that PLK1 inhibitor synergizes with mTOR inhibitor to induce synergistic anti-tumor effect in colorectal cancer by antagonizing a compensatory Myc induction. These findings identify a novel pathway in human cancer and CSC activation and provide a therapeutic strategy for targeting Myc-associated tumorigenesis and therapeutic resistance.
2013-07-31 | GSE30669 | GEO
Project description:Polo-Like Kinase 1 (PLK1), a serine/threonine kinase involved in cell cycle regulation at the G2/M transition, is associated with high-risk neuroblastoma (NB) and unfavorable patient outcome. Recently, we and others demonstrated that PLK1 is a potential drug target in neuroblastoma and reported antitumoral actvity of the PLK1 inhibitor BI2536 in preclinical models of NB. We here analyzed the effects of the ATP-competitive PLK1 inhibitor GSK461364 on typical tumorigenic properties of preclinical in vitro and in vivo models of NB. Treatment of NB cells with GSK461364 resulted in decreased cell viability and reduction of proliferative capacity, and led to cell cycle arrest and massive induction of apoptosis. These phenotypic consequences were observed at low-dose nanomolar levels and were independent of the MYCN copy number status of the cell lines. In vivo treatment with GSK461364 led to a strong delay in tumor development and to a highly significant increase in survival in the treatment group. These preclinical findings highlight the promise of PLK1 inhibitors as novel agents for NB and serve as rationale to move forward with early phase clinical trials in children.
2015-03-21 | GSE67102 | GEO
Project description:Polo-like kinase 1 (Plk1) is an important protein kinase for checkpoint recovery and adaptation in response to DNA damage and replication stress. However, although Plk1 is present in S phase, little is known about its localization and function during unperturbed DNA replication. Using Xenopus laevis egg extracts, mimicking early embryonic replication, we developed a Plk1 chromatin immunoprecipitation approach followed by a proteomic shotgun analysis (XChIP-MS) to identify Plk1 interactions with chromatin and with specific nuclear proteins. We purified and cross-linked nuclei after pre-RC assembly before the start of DNA replication, or later during DNA replication. The DNA was fractionated by sonication and immunoprecipited using anti Plk1 or control antibodies then proteins were analyzed by nanoLC/MS/MS.
2021-08-25 | PXD022440 | Pride
Project description:Polo-like kinase 1 (Plk1) is an important protein kinase for checkpoint recovery and adaptation in response to DNA damage and replication stress. However, although Plk1 is present in S phase, little is known about its localization and function during unperturbed DNA replication. Here we used a previously described Chromatin Mass spectrometry (Chromass) protocol (Project PXD000490) to compare the protein recruitment on chromatin in Xenopus egg extracts during unperturbed DNA replication in the presence or after Plk1 depletion from the extract.
2021-08-25 | PXD022572 | Pride