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PLK1 inhibition selectively induces apoptosis in ARID1A deficient cells through uncoupling of oxygen consumption from ATP production

ABSTRACT: PLK1 inhibition selectively induces apoptosis in ARID1A deficient cells through uncoupling of oxygen consumption from ATP production

PROVIDER: PRJNA798434 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR17657900_1.fastq.gz	Fastqsanger.gz
	SRR17657900_2.fastq.gz	Fastqsanger.gz
	SRR17657901_1.fastq.gz	Fastqsanger.gz
	SRR17657901_2.fastq.gz	Fastqsanger.gz
	SRR17657902_1.fastq.gz	Fastqsanger.gz

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PLK1 inhibition selectively induces apoptosis in ARID1A deficient cells through uncoupling of oxygen consumption from ATP production

Project description:Inhibitors of the mitotic kinase PLK1 yield objective responses in a subset of refractory cancers. However, PLK1 overexpression in cancer does not correlate with drug sensitivity, and the clinical development of PLK1 inhibitors has been hampered by the lack of patient selection marker. Using a high-throughput chemical screen, we discovered that cells deficient for the tumor suppressor ARID1A are highly sensitive to PLK1 inhibition. Interestingly this sensitivity was unrelated to canonical functions of PLK1 in mediating G2-M cell cycle transition. Instead, a whole-genome CRISPR screen revealed PLK1 inhibitor sensitivity in ARID1A deficient cells to be dependent on the mitochondrial translation machinery. We find that ARID1A knock-out (KO) cells have an unusual mitochondrial phenotype with aberrant biogenesis, increased oxygen consumption/ expression of oxidative phosphorylation genes, but without increased ATP production. Using expansion microscopy and biochemical fractionation, we see that a subset of PLK1 localizes to the mitochondria in interphase cells. Inhibition of PLK1 in ARID1A KO cells further uncouples oxygen consumption from ATP production, with subsequent membrane depolarization and apoptosis. Knockdown of specific subunits of the mitochondrial ribosome reverses PLK1-inhibitor induced apoptosis in ARID1A deficient cells, confirming specificity of the phenotype. Together, these findings highlight a novel interphase role for PLK1 in maintaining mitochondrial fitness under metabolic stress, and a strategy for therapeutic use of PLK1 inhibitors. To translate these findings, we describe a quantitative microscopy assay for assessment of ARID1A protein loss, which could offer a novel patient selection strategy for the clinical development of PLK1 inhibitors in cancer.

2022-03-08 | PXD031110 | Pride

PLK1 inhibition selectively induces apoptosis in ARID1A deficient cells through uncoupling of oxygen consumption from ATP production

Project description:We have identified a synthetically lethal relationship between the loss of chromatin modulator, ARID1A, and the inhibition of PLK1 kinase through a mechanism that involves mitochondrial dysfunction. Using normal gastric epithelium cell line, GES1, we performed a comparative gene expression analysis comparing the various permutations of wild type (WT) and ARID1A knockout (KO) genotypes and untreated cells or those treated with PLK1 inhibitor,Volasertib. Consistent with ARID1A's role as a chromatin modulator, there was widespread gene expression modulation observed when comparing the WT cells with the ARID1A KO cells. In particular, we noted that oxidative phosphorylation and ROS pathway genes were enriched in ARID1A KO cells compared to wild type cells. Volasertib treatment appeared to exacerbate the effects on gene expression induced by ARID1A KO. We also investigated how ARID1A KO and Volasertib treatment specifically modulated the expression of mitochondrial encoded genes using a more recent human genome build, hg38 (as opposed to hg19), that enabled the correct alignment of these mitochondrial genes. For this analysis, in addition to GES1s, we used the ovarian cancer cell line, OVCAR3. To answer the question of which genes facilitate preferential cell killing of Volasertib-treated ARID1A KO cells, using normal breast epithelial cells, MCF10A, we performed a genome-wide CRISPR screen using the Brunello library. We identified many genes whose knockout made ARID1A KO cells resistant to Volasertib, many of which were involved in mitochondrial process.

2022-07-06 | GSE193942 | GEO

PLK1 inhibition selectively induces apoptosis in ARID1A deficient cells through uncoupling of oxygen consumption from ATP production -- DATA HAVE BEEN MOVED TO GSE193942

Project description:See GSE193942

2022-03-06 | GSE193943 | GEO

Expression data of human neuroblastoma SK-N-AS treated with the PLK1 inhibitor GSK461364

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

Expression profile in Plk1(+/-) aortas

Project description:Transcriptional profiling of mouse aortas comparing control wild-type animals with aortas from three different Plk1(+/-) mice. Goal was to determine the effects of Plk1 haploinsufficiency in aorta expression profiles.

2017-07-01 | GSE85199 | GEO

Genetic enhancers of partial PLK1 inhibition reveal hypersensitivity to kinetochore perturbations

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

PLK1 signaling coopereates with estrogen receptor-dependent gene transcription.

Project description:Analysis of MCF7 breast cancer cells treated with estadiol for 6 h in presence or absence of the specific PLK1 inhibitor BI2536. Together with CHIP and global phosphoproteome data, the results demonstrate a key role of PLK1 in the estrogen receptor-mediated gene response. Hormone-deprived MCF7 cells were pretreated with BI2536 or vehicle (DMSO) followed by induction with estradiol (E2) or vehicle (ethanol). RNA of each condition was analysed in triplicate on an Agilent Human genome 4x44k v2 microarray [note: MCF7_DMSO_E2_rep3 sample was a clear technical outlier (poor hybridization), and was therefore excluded from the further analysis/this record].

2014-01-01 | E-GEOD-46856 | biostudies-arrayexpress

Epigenome analysis of normal and PLK1 knockdown samples

Project description:The Illumina Infinium 850k Human DNA methylation Beadchip was used to obtain DNA methylation profiles in normal and PLK1 knockdown DU145 cell samples. Samples included normal and PLK1 knockdown DU145 cell samples, Each sample is repeated three times.

2022-02-22 | GSE167261 | GEO

Role of PLK1 in epithelial-mesenchymal transition in human melanoma

Project description:Polo-like kinase 1 (PLK1), a serine/threonine kinase and important cell cycle regulator, is overexpressed in melanoma and its expression has been associated with poor disease prognosis. PLK1 has been shown to interact with NUMB, a NOTCH antagonist. However, the exact role of PLK1-NUMB-NOTCH axis in epithelial-mesenchymal transition (EMT) and melanoma progression is unclear. In this study, Affymetrix microarray analysis was performed to determine differentially expressed genes following doxycyclin induced shRNA-mediated knockdown of PLK1 in human melanoma cells that showed significant modulations in EMT and metastasis related genes.

2024-01-01 | GSE237385 | GEO

PLK1 signaling coopereates with estrogen receptor-dependent gene transcription.

2014-01-01 | GSE46856 | GEO