Novel inhibitors targeting PPM1D phosphatase potently suppress cancer cell proliferation

Ogasawara, Sari; Kiyota, Yuhei; Chuman, Yoshiro; Kowata, Ayano; Yoshimura, Fumihiko; Tanino, Keiji; Kamada, Rui; Sakaguchi, Kazuyasu

doi:10.1016/j.bmc.2015.08.042

Cited by 34 publications

(33 citation statements)

References 23 publications

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“…hsa-mir-4746 has a common target, PPM1D (Protein phosphatase 1D), in both breast and lung cancer. Because of its function in protein dephosphorylation, PPM1D is involved in G2/M transition of mitotic cell cycle and suppression of cell proliferation in cancer [53]. The importance of the functions of their target genes in gene/cellular regulation suggests abnormally expressed hsa-mir-1269a, hsa-mir-4652, and hsamir-4746 may contribute to the development of corresponding cancer types.…”

Section: Resultsmentioning

confidence: 99%

Identification of key differentially expressed MicroRNAs in cancer patients through pan-cancer analysis

Dingerdissen

Gupta

et al. 2018

Computers in Biology and Medicine

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microRNAs (miRNAs) functioning in gene silencing have been associated with cancer progression. However, common abnormal miRNA expression patterns and their potential roles in cancer have not yet been evaluated. To account for individual differences between patients, we retrieved miRNA sequencing data for 575 patients with both tumor and adjacent nontumorous tissues from 14 cancer types from The Cancer Genome Atlas (TCGA). We then performed differential expression analysis using DESeq2 and edgeR. Results showed that cancer types can be grouped based on the distribution of miRNAs with different expression patterns between tumor and non-tumor samples. We found 81 significantly differentially expressed miRNAs (SDEmiRNAs) in a single cancer. We also found 21 key SDEmiRNAs (nine over-expressed and 12 under-expressed) associated with at least eight cancers each and enriched in more than 60% of patients per cancer, including four newly identified SDEmiRNAs (hsa-mir-4746, hsa-mir-3648, hsa-mir-3687, and hsa-mir-1269a). The downstream effects of these 21 SDEmiRNAs on cellular function were evaluated through enrichment and pathway analysis of 7,186 protein-coding gene targets mined from literature reports of differential expression of miRNAs in cancer. This analysis enables identification of SDEmiRNA functional similarity in cell proliferation control across a wide range of cancers, and assembly of common regulatory networks over cancer-related pathways. These findings were validated by construction of a regulatory network in the PI3K pathway. This study provides evidence for the value of further analysis of SDEmiRNAs as potential biomarkers and therapeutic targets for cancer diagnosis and treatment.

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Section: Resultsmentioning

confidence: 99%

Identification of key differentially expressed MicroRNAs in cancer patients through pan-cancer analysis

Dingerdissen

Gupta

et al. 2018

Computers in Biology and Medicine

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“…Compared to previous compounds, SPI-001 and its analogue SL-176 were determined as non-competitive inhibitors of recombinant WIP1 with IC 50 = 110 and 86.9 nM, respectively [90, 91]. Moreover, SPI-001 was determined to be approximately 50-fold more specific against WIP1 than to another PP2C phosphatase, PPM1A [90].…”

Section: Small-molecule Inhibitors Of Wip1mentioning

confidence: 99%

“…Moreover, SPI-001 was determined to be approximately 50-fold more specific against WIP1 than to another PP2C phosphatase, PPM1A [90]. Both SPI-001 and SL-176 suppressed the cell proliferation in human breast cancer MCF7 cells with overexpressed wild-type PPM1D in a dose-dependent manner [91]. In human colorectal carcinoma HCT-116 cells expressing truncated WIP1, treatment with SPI-001 did not affect cell proliferation but combined treatment with SPI-001 and doxorubicin enhanced inhibition of cell growth through the increased phosphorylation of p53 at Ser15 [92].…”

Section: Small-molecule Inhibitors Of Wip1mentioning

confidence: 99%

WIP1 phosphatase as pharmacological target in cancer therapy

2017

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DNA damage response (DDR) pathway protects cells from genome instability and prevents cancer development. Tumor suppressor p53 is a key molecule that interconnects DDR, cell cycle checkpoints, and cell fate decisions in the presence of genotoxic stress. Inactivating mutations in TP53 and other genes implicated in DDR potentiate cancer development and also influence the sensitivity of cancer cells to treatment. Protein phosphatase 2C delta (referred to as WIP1) is a negative regulator of DDR and has been proposed as potential pharmaceutical target. Until recently, exploitation of WIP1 inhibition for suppression of cancer cell growth was compromised by the lack of selective small-molecule inhibitors effective at cellular and organismal levels. Here, we review recent advances in development of WIP1 inhibitors and discuss their potential use in cancer treatment.

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“…These platforms are the successors of double‐knockout array technology used in yeast to identify genetic interactions for 90% of all genes (Tong et al , ; Costanzo et al , , ). While these methods have the power to directly test hypothesized genetic interactions, technological constraints have limited individual combinatorial sgRNA studies to measuring interactions for only a small fraction of all pairs of human genes (Ogasawara et al , ; Wong et al , ; Han et al , ; Shen et al , ; Horlbeck et al , ). Ascertaining appropriate gene pairs for such phenotyping is not trivial, especially for synthetic interactions where neither genetic perturbation exhibits an effect on its own, although algorithms to overcome this challenge are under development (Medina & Goodin, ; preprint: Deshpande et al , ).…”

Section: Introductionmentioning

confidence: 99%

High‐resolution mapping of cancer cell networks using co‐functional interactions

Boyle

Pritchard

Greenleaf

2018

Molecular Systems Biology

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Powerful new technologies for perturbing genetic elements have recently expanded the study of genetic interactions in model systems ranging from yeast to human cell lines. However, technical artifacts can confound signal across genetic screens and limit the immense potential of parallel screening approaches. To address this problem, we devised a novel PCA‐based method for correcting genome‐wide screening data, bolstering the sensitivity and specificity of detection for genetic interactions. Applying this strategy to a set of 436 whole genome CRISPR screens, we report more than 1.5 million pairs of correlated “co‐functional” genes that provide finer‐scale information about cell compartments, biological pathways, and protein complexes than traditional gene sets. Lastly, we employed a gene community detection approach to implicate core genes for cancer growth and compress signal from functionally related genes in the same community into a single score. This work establishes new algorithms for probing cancer cell networks and motivates the acquisition of further CRISPR screen data across diverse genotypes and cell types to further resolve complex cellular processes.

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Novel inhibitors targeting PPM1D phosphatase potently suppress cancer cell proliferation

Cited by 34 publications

References 23 publications

Identification of key differentially expressed MicroRNAs in cancer patients through pan-cancer analysis

Identification of key differentially expressed MicroRNAs in cancer patients through pan-cancer analysis

WIP1 phosphatase as pharmacological target in cancer therapy

High‐resolution mapping of cancer cell networks using co‐functional interactions

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