Therapeutic opportunities for PLK1 inhibitors: Spotlight on BRCA1-deficiency and triple negative breast cancers

García, Iris Alejandra; Garro, Cintia; Fernández, Elmer; Soria, Gastón

doi:10.1016/j.mrfmmm.2020.111693

Cited by 15 publications

(16 citation statements)

References 109 publications

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“…Thus, targeting those proteins is a promising approach in breast cancer medication. In breast cancer (BC) patients, a high expression level of PLK1 was noted as an essential marker for cancer progression and metastasis with a poor prognosis [37,38]. PLK1 involves in G2/M progression.…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics Analysis Confirms the Target Protein Underlying Mitotic Catastrophe of 4T1 Cells under Combinatorial Treatment of PGV-1 and Galangin

et al. 2021

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Pentagamavunon-1 (PGV-1), a potential chemopreventive agent with a strong cytotoxic effect, modulates prometaphase arrest. Improvement to get higher effectiveness of PGV-1 is a new challenge. A previous study reported that the natural compound, galangin, has antiproliferative activity against cancer cells with a lower cytotoxicity effect. This study aims to develop a combinatorial treatment of PGV-1 and galangin as an anticancer agent with higher effectiveness than a single agent. In this study, 4T1, a TNBC model cell, was treated with a combination of PGV-1 and galangin. As a result, PGV-1 and galangin showed a cytotoxic effect with IC50 values of 8 and 120 µM, respectively. Combining those chemicals has a synergistic impact, as shown by the combination index (CI) value of 1. Staining with the May Grunwald-Giemsa reagent indicated mitotic catastrophe evidence, characterized by micronuclear and multinucleated morphology. Moreover, the senescence percentage was higher than the single treatment. Furthermore, bioinformatics investigations showed that PGV-1 and galangin target CDK1, PLK1, and AURKB, overexpression proteins in TNBC that are essential in regulating cell cycle arrest. In conclusion, the combination of PGV-1 and galangin exhibit a synergistic effect and potential to be a chemotherapeutic drug by the mechanism of mitotic catastrophe and senescence induction.

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Section: Discussionmentioning

confidence: 99%

Bioinformatics Analysis Confirms the Target Protein Underlying Mitotic Catastrophe of 4T1 Cells under Combinatorial Treatment of PGV-1 and Galangin

et al. 2021

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“…PLK1 is a cell cycle kinase that participates in eukaryotes mitosis and can be used as a biomarker and potential therapeutic target in oncology. 33 It has been reported that overexpression of PLK1 can promote the progression of breast cancer, 33 renal cell carcinoma, 34 gastric cancer. 35 With regard to the study of PLK1 in OS, Zhu et al found that the proliferation of OS cells was inhibited with the intervention of PLK1 expression.…”

Section: Discussionmentioning

confidence: 99%

<p>MiR-1224-5p Activates Autophagy, Cell Invasion and Inhibits Epithelial-to-Mesenchymal Transition in Osteosarcoma Cells by Directly Targeting PLK1 Through PI3K/AKT/mTOR Signaling Pathway</p>

Jin¹,

Jin²,

Zhuo³

et al. 2020

OTT

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“…BUB1B, which blocks the activation of APC Cdc20 , is the central component of the mitotic checkpoint for spindle assembly, and it was proved overexpressed in breast cancer and acts as a oncogene (Koyuncu et al, 2020). PLK1, as a member of polo-like kinase family, is involved in mitotic entry, centrosome maturation, spindle assembly, and cytokinesis process (Golsteyn et al, 1995;García et al, 2020). Results from CRISPR-cas9 screening suggested that knocking out these genes leads to cell death in breast cancer of all subtypes, and inhibitors targeting these genes may be potential therapeutic strategies for breast cancer.…”

Section: Discussionmentioning

confidence: 99%

CRISPR-cas9 Screening Identified Lethal Genes Enriched in Cell Cycle Pathway and of Prognosis Significance in Breast Cancer

Sun

Wang

Chen

et al. 2021

Front. Cell Dev. Biol.

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BackgroundLethal genes have not been systematically analyzed in breast cancer which may have significant prognostic value. The current study aims to investigate vital genes related to cell viability by analyzing the CRISPR-cas9 screening data, which may provide novel therapeutic target for patients.MethodsGenes differentially expressed between tumor and normal tissue from the Cancer Genome Atlas (TCGA) and genes related to cell viability by CRISPR-cas9 screening from Depmap (Cancer Dependency Map) were overlapped. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analysis was conducted to identify which pathways of overlapped genes were enriched. GSE21653 set was randomized into training and internal validation dataset at a ratio of 3:1, and external validation was performed in GSE20685 set. The least absolute shrinkage and selection operator (LASSO) regression was used to construct a signature to predict recurrence-free survival (RFS) of breast cancer patients. Univariate and multivariate Cox regression were used to evaluate the prognostic value of this signature. Differentially expressed genes (DEGs) between high-risk and low-risk patients were then analyzed to identify the main pathways regulated by this signature. Weighted correlation network analysis (WGCNA) was conducted to recognize modules correlated with high risk. Enrichment analysis was then used to identify pathways regulated by genes shared in the overlapped genes, DEGs, and WGCNA.ResultsA total of 86 oncogenes were upregulated in TCGA database and overlapped with lethal genes in Depmap database, which were enriched in cell cycle pathway. A total of 51 genes were included in the gene signature based on LASSO regression, and the median risk score of 2.36 was used as cut-off to separate low-risk patients from high-risk patients. High-risk patients showed worse RFS compared with low-risk patients in internal training, internal validation, and external validation dataset. Time-dependent receiver operating characteristic curves of 3 and 5 years indicated that risk score was superior to tumor stage, age, and PAM50 in both entire and external validation datasets. Cell cycle was the main different pathway between the high-risk and low-risk groups. Meanwhile, cell cycle was also the main pathway enriched in the 25 genes which were shared among 86 genes, DEGs, and WGCNA.ConclusionCell cycle pathway, identified by CRISPR-cas9 screening, was a key pathway regulating cell viability, which has significant prognostic values and can serve as a new target for breast cancer patient treatment.

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Therapeutic opportunities for PLK1 inhibitors: Spotlight on BRCA1-deficiency and triple negative breast cancers

Cited by 15 publications

References 109 publications

Bioinformatics Analysis Confirms the Target Protein Underlying Mitotic Catastrophe of 4T1 Cells under Combinatorial Treatment of PGV-1 and Galangin

Bioinformatics Analysis Confirms the Target Protein Underlying Mitotic Catastrophe of 4T1 Cells under Combinatorial Treatment of PGV-1 and Galangin

<p>MiR-1224-5p Activates Autophagy, Cell Invasion and Inhibits Epithelial-to-Mesenchymal Transition in Osteosarcoma Cells by Directly Targeting PLK1 Through PI3K/AKT/mTOR Signaling Pathway</p>

CRISPR-cas9 Screening Identified Lethal Genes Enriched in Cell Cycle Pathway and of Prognosis Significance in Breast Cancer

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