Dataset Information

Downregulation of PARP1 transcription by CDK4/6 inhibitors sensitizes human lung cancer cells to anticancer drug-induced death by impairing OGG1-dependent base excision repair.

ABSTRACT: Hallmarks of cancer cells include uncontrolled growth and rapid proliferation; thus, cyclin-dependent kinases are a therapeutic target for cancer treatment. Treating non-small lung cancer cells with sublethal concentrations of the CDK4/6 inhibitors, ribociclib (LEE011) and palbociclib (PD0332991), which are approved by the FDA for anticancer therapies, caused cell cycle arrest in the G1 phase and suppression of poly(ADP-ribose) polymerase 1 (PARP1) transcription by inducing recruitment of the RB1-E2F1-HDAC1-EZH2 repressive complex to the PARP1 promoter. Downregulation of PARP1 made cancer cells vulnerable to death triggered by the anticancer drugs (WP631 and etoposide) and H₂O₂. All agents brought about redox imbalance and DNA strand breaks. The lack of PARP1 and poly(ADP-ribosyl)ation impaired the 8-oxoguanine glycosylase (OGG1)-dependent base excision DNA repair pathway, which is critical for maintaining the viability of cells treated with CDK4/6 inhibitors during oxidative stress. Upon G1 arrest of PARP1 overexpressing cells, OGG1 formed an immunoprecipitable complex with PARP1. Similar to cells with downregulated PARP1 expression, inhibition of PARP1 or OGG1 in PARP1 overexpressing cells resulted in DNA damage and decreased viability. Thus, PARP1 and OGG1 act in the same regulatory pathway, and PARP1 activity is required for OGG1-mediated repair of oxidative DNA damage in G1-arrested cells. In conclusion, the action of CDK4/6 inhibitors is not limited to the inhibition of cell growth. CDK4/6 inhibitors also lead to accumulation of DNA damage by repressing PARP1 in oxidatively stressed cells. Thus, CDK4/6 inhibitors sensitize G1-arrested cells to anticancer drugs, since these cells require PARP1-OGG1 functional interaction for cell survival.

SUBMITTER: Tempka D

PROVIDER: S-EPMC5975074 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Downregulation of PARP1 transcription by CDK4/6 inhibitors sensitizes human lung cancer cells to anticancer drug-induced death by impairing OGG1-dependent base excision repair.

Tempka Dominika D Tokarz Paulina P Chmielewska Kinga K Kluska Magdalena M Pietrzak Julita J Rygielska Żaneta Ż Virág László L Robaszkiewicz Agnieszka A

Redox biology 20171229

Hallmarks of cancer cells include uncontrolled growth and rapid proliferation; thus, cyclin-dependent kinases are a therapeutic target for cancer treatment. Treating non-small lung cancer cells with sublethal concentrations of the CDK4/6 inhibitors, ribociclib (LEE011) and palbociclib (PD0332991), which are approved by the FDA for anticancer therapies, caused cell cycle arrest in the G1 phase and suppression of poly(ADP-ribose) polymerase 1 (PARP1) transcription by inducing recruitment of the RB ...[more]

PMID: 29306194

Similar Datasets

Project description:Purpose: The aim of this study is to evaluate the global gene expression induced by OGG1-BER product 8-oxoG in mouse airways. Methods: RNA extracted from individual mouse lungs (experimental group: n=5) were pooled and a total 1 M-NM-<g RNA was used for Next-Generation Sequencing (NGS) analyses on an Illumina HiSeq 1000 sequencing system. Sequence analysis were performed in duplicate. First- and second-strand synthesis, adapter ligation and amplification of the library were performed using the Illumina TruSeq Sample Preparation Kit as recommended by the manufacturer (Illumina). Library quality was evaluated by using an Agilent DNA-1000 chip on an Agilent 2100 Bioanalyzer. Library DNA templates were quantitated by qPCR using known reference starndards. Cluster formation of the library of DNA templates was performed using the TruSeq PE Cluster Kit v3 (Illumina) and the Illumina cBot workstation. Paired-end, 50-base sequencing was performed with a TruSeq SBS kit v3 (Illumina) on the Illumina HiSeq 1000 by protocols defined by the manufacturer. Base call conversion to sequence reads was performed using CASAVA-1.8.2. Sequence data were analyzed with the Bowtie2, Tophat2 and GFOLD programs. Processed data are presented as reads per kilobase transcript per million (RPKM), normalized to the experimental control (RNA from saline-challenged lungs) and reported as fold change (test/control). Results: We mapped an average of 24.76 million sequence reads per sample and identified 23,337 transcripts in total RNA extracted from lungs of Balb/cJ mice as described in Methods. Approximately 10% of the transcripts showed differential expression between the saline-challenged control and 8-oxoguanine-challeged mouse lungs, with a fold change M-bM-^IM-%3.0. We validated the expression changes of 7 selected pro-inflammatory cytokines and chemokines of interest for our studies by qRT-PCR. Hierarchical clustering followed by Protein ANalysis THrough Evolutionary Relationships database (PANTHER) analysis of differentially expressed genes. Results showed overrepresentation of various biological functions (GO terms) including immune system process (GO:0002376; p=5.24e-12) among others. Pathway analysis (PANTHER) indicated that the most overrepresented pathway was inflammation mediated by chemokine and cytokine (P00031, p=<0.01). In addition to gene expression analysis, we confirmed OGG1M-bM-^@M-"8-oxoG-dependent RAS activation in lungs by active RAS pull-down assays, airways neutrophil accumulation by bronchoalveolar lavage fluid (BALF) differential cell counts and airway inflammation by histological examination (H&E staining) of lung sections. Conclusions: This is the first study at the whole-transcriptome level to show induction of innate immune response gene expression in mouse lungs after exposure to OGG1-BER product 8-oxoG. Balb/cJ mice (5 per group) were intranasally challenged with 8-oxoguanine (1 M-BM-5M, 60 M-BM-5l) for 30, 60 and 120 min. Control group mice were intranasally challenged with saline (60 M-BM-5l). RNA from individual mice whithin the same group was pooled and subjected to deep-sequencing analysis in duplicate using NGS on an Illumina HiSeq 1000 sequencing system. After alignment and processing, the resulting RPKM from treatment groups (8-oxoG-challenged) were normalized to the control group (saline-challenged).

Dataset Information

Downregulation of PARP1 transcription by CDK4/6 inhibitors sensitizes human lung cancer cells to anticancer drug-induced death by impairing OGG1-dependent base excision repair.

Publications

Downregulation of PARP1 transcription by CDK4/6 inhibitors sensitizes human lung cancer cells to anticancer drug-induced death by impairing OGG1-dependent base excision repair.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets