Dataset Information

Ym155 Induces Oxidative Stress-Mediated DNA Damage and Cell Cycle Arrest, and Causes Programmed Cell Death in Anaplastic Thyroid Cancer Cells.

ABSTRACT: Anaplastic thyroid cancer (ATC) is one of the most lethal malignancies with a median survival time of about 4 months. Currently, there is no effective treatment, and the development of new therapies is an important and urgent issue for ATC patients. YM155 is a small molecule that was identified as the top candidate in a high-throughput screen of small molecule inhibitors performed against a panel of ATC cell lines by the National Cancer Institute. However, there were no follow-up studies investigating YM155 in ATC. Here, we determined the effects of YM155 on ATC and human primary benign thyroid cell (PBTC) survival with alamarBlue assay. Our data show that YM155 inhibited proliferation of ATC cell lines while sparing normal thyroid cells, suggesting a high therapeutic window. YM155-induced DNA damage was detected by measuring phosphorylation of ?-H2AX as a marker for DNA double-strand breaks. The formamidopyrimidine-DNA glycosylase (FPG)-modified alkaline comet assay in conjunction with reactive oxygen species (ROS) assay and glutathione (GSH)/glutathione (GSSG) assay suggests that YM155-mediated oxidative stress contributes to DNA damage. In addition, we provide evidence that YM155 causes cell cycle arrest in S phase and in the G2/M transition and causes apoptosis, as seen with flow cytometry. In this study, we show for the first time the multiple effects of YM155 in ATC cells, furthering a potential therapeutic approach for ATC.

SUBMITTER: Xu Q

PROVIDER: S-EPMC7920419 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Ym155 Induces Oxidative Stress-Mediated DNA Damage and Cell Cycle Arrest, and Causes Programmed Cell Death in Anaplastic Thyroid Cancer Cells.

Xu Qinqin Q Mackay Ryan P RP Xiao Adam Y AY Copland John A JA Weinberger Paul M PM

International journal of molecular sciences 20210216 4

Anaplastic thyroid cancer (ATC) is one of the most lethal malignancies with a median survival time of about 4 months. Currently, there is no effective treatment, and the development of new therapies is an important and urgent issue for ATC patients. YM155 is a small molecule that was identified as the top candidate in a high-throughput screen of small molecule inhibitors performed against a panel of ATC cell lines by the National Cancer Institute. However, there were no follow-up studies investi ...[more]

PMID: 33669447

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Project description:Background Since anaplastic thyroid carcinoma (ATC) has rapid progression and a poor outcome, identification of the key genes and underlying mechanisms of ATC is required. Methods Gene expression profiles of GSE29265 and GSE33630 were available from the Gene Expression Omnibus database. The two profile datasets included 19 ATC tissues, 55 normal thyroid tissues and 59 papillary thyroid cancer (PTC) tissues. Differentially expressed genes (DEGs) between ATC tissues and normal thyroid tissues as well as ATC tissues and PTC tissues were identified using the GEO2R tool. Common DEGs between the two datasets were selected via Venn software online. Then, we applied the Database for Annotation, Visualization and Integrated Discovery for Kyoto Encyclopedia of Gene and Genome pathway and gene ontology (GO) analyses. Additionally, protein-protein interactions (PPIs) of these DEGs were visualized via Cytoscape with Search Tool for the Retrieval of Interacting Genes. In the PPI networks analyzed by the Molecular Complex Detection plug-in, all 54 upregulated core genes were selected. Furthermore, Kaplan-Meier analysis was applied to analyze overall survival based on these 54 genes. Then, we used the DrugBank database to identify drug relationships for the 54 genes. Additionally, we validated the correlations between genes enriched in pathways and genes identified as prognosis biomarkers of THCA by Gene Expression Profiling Interactive Analysis. Results Four genes (CCNB1, CCNB2, CDK1 and CHEK1) involved cell cycle arrest and DNA repair were significantly enriched in the G2/M phase of the cell cycle pathway and before G2 phase arrest of the P53 pathway. Inhibitors of CHEK1, CDK1 and TOP2A were identified in the DrugBank database. ANLN, DEPDC1, KIF2C, CENPN, TACC3 CCNB2 and CDC6 were hypothesized to be prognostic biomarkers of ATC. Furthermore, CCNB1, CCNB2, CDK1 and CHEK1 were significantly positively associated with these prognosis genes. Conclusions CCNB1, CCNB2, CDK1 and CHEK1 may be key genes involved cell cycle arrest and DNA damage repair in ATC. Further studies are required to confirm the contributions of the identified genes to ATC progression and survival.

Project description:BackgroundAnaplastic thyroid carcinoma (ATC) accounts for only 3% of thyroid cancers, yet strikingly, it accounts for almost 40% of thyroid cancer deaths. Currently, no effective therapies exist. In an effort to identify ATC-specific therapeutic targets, we analyzed global gene expression data from multiple studies to identify ATC-specific dysregulated genes.MethodsThe National Center for Biotechnology Information Gene Expression Omnibus database was searched for high-throughput gene expression microarray studies from human ATC tissue along with normal thyroid and/or papillary thyroid cancer (PTC) tissue. Gene expression levels in ATC were compared with normal thyroid or PTC using seven separate comparisons, and an ATC-specific gene set common in all seven comparisons was identified. We investigated these genes for their biological functions and pathways.ResultsThere were three studies meeting inclusion criteria, (including 32 ATC patients, 69 PTC, and 75 normal). There were 259 upregulated genes and 286 downregulated genes in ATC with at least two-fold change in all seven comparisons. Using a five-fold filter, 36 genes were upregulated in ATC, while 40 genes were downregulated. Of the 10 top globally upregulated genes in ATC, 4/10 (MMP1, ANLN, CEP55, and TFPI2) are known to play a role in ATC progression; however, 6/10 genes (TMEM158, CXCL5, E2F7, DLGAP5, MME, and ASPM) had not been specifically implicated in ATC. Similarly, 3/10 (SFTA3, LMO3, and C2orf40) of the most globally downregulated genes were novel in this context, while 7/10 genes (SLC26A7, TG, TSHR, DUOX2, CDH1, PDE8B, and FOXE1) have been previously identified in ATC. We experimentally validated a significant correlation for seven transcription factors (KLF16, SP3, ETV6, FOXC1, SP1, EGFR1, and MAFK) with the ATC-specific genes using microarray analysis of ATC cell lines. Ontology clustering of globally altered genes revealed that "mitotic cell cycle" is highly enriched in the globally upregulated gene set (44% of top upregulated genes, p-value <10-30).ConclusionsBy focusing on globally altered genes, we have identified a set of consistently altered biological processes and pathways in ATC. Our data are consistent with an important role for M-phase cell cycle genes in ATC, and may provide direction for future studies to identify novel therapeutic targets for this disease.

Dataset Information

Ym155 Induces Oxidative Stress-Mediated DNA Damage and Cell Cycle Arrest, and Causes Programmed Cell Death in Anaplastic Thyroid Cancer Cells.

Publications

Ym155 Induces Oxidative Stress-Mediated DNA Damage and Cell Cycle Arrest, and Causes Programmed Cell Death in Anaplastic Thyroid Cancer Cells.

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