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Phosphodiesterase 10A (PDE10A) as a novel target to suppress β-catenin and RAS signaling in ovarian cancer

ABSTRACT: Phosphodiesterase 10A (PDE10A) as a novel target to suppress β-catenin and RAS signaling in ovarian cancer

PROVIDER: PRJNA690803 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13388848_1.fastq.gz	Fastqsanger.gz
	SRR13388848_2.fastq.gz	Fastqsanger.gz
	SRR13388849_1.fastq.gz	Fastqsanger.gz
	SRR13388849_2.fastq.gz	Fastqsanger.gz
	SRR13388850_1.fastq.gz	Fastqsanger.gz

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Phosphodiesterase 10A (PDE10A) as a novel target to suppress β-catenin and RAS signaling in epithelial ovarian cancer.

Project description:A leading theory for ovarian carcinogenesis proposes that inflammation associated with incessant ovulation is a driver of oncogenesis. Consistent with this theory, nonsteroidal anti-inflammatory drugs (NSAIDs) exert promising chemopreventive activity for ovarian cancer. Unfortunately, toxicity is associated with long-term use of NSAIDs due to their cyclooxygenase (COX) inhibitory activity. Previous studies suggest the antineoplastic activity of NSAIDs is COX independent, and rather may be exerted through phosphodiesterase (PDE) inhibition. PDEs represent a unique chemopreventive target for ovarian cancer given that ovulation is regulated by cyclic nucleotide signaling. Here we evaluate PDE10A as a novel therapeutic target for ovarian cancer. Analysis of The Cancer Genome Atlas (TCGA) ovarian tumors revealed PDE10A overexpression was associated with significantly worse overall survival for patients. PDE10A expression also positively correlated with the upregulation of oncogenic and inflammatory signaling pathways. Using small molecule inhibitors, Pf-2545920 and a novel NSAID-derived PDE10A inhibitor, MCI-030, we show that PDE10A inhibition leads to decreased ovarian cancer cell growth and induces cell cycle arrest and apoptosis. We demonstrate these pro-apoptotic properties occur through PKA and PKG signaling by using specific inhibitors to block their activity. PDE10A genetic knockout in ovarian cancer cells through CRISP/Cas9 editing lead to decreased cell proliferation, colony formation, migration and invasion, and in vivo tumor growth. We also demonstrate that PDE10A inhibition leads to decreased Wnt-induced β-catenin nuclear translocation, as well as decreased EGF-mediated activation of RAS/MAPK and AKT pathways in ovarian cancer cells. These findings implicate PDE10A as novel target for ovarian cancer chemoprevention and treatment.

| S-EPMC9632086 | biostudies-literature

Phosphodiesterase 10A (PDE10A) as a novel target to suppress β-catenin and RAS signaling in ovarian cancer

Project description:The goal of this study was to investigate molecular pathways associated with PDE10A in ovarian cancer. We used CRISPR/Cas9 to knockout PDE10A in SKOV3 cells. We used the Illumina NextSeq500 to generate between 30-35 million paired end 75bp sequencing reads per sample for transcript level abundance.

2022-01-10 | GSE164474 | GEO

Phosphodiesterase 10A inactivation protects against doxorubicin-induced cardiotoxicity and concomitantly inhibits tumor growth

Project description:Phosphodiesterase 10A inactivation protects against doxorubicin-induced cardiotoxicity and concomitantly inhibits tumor growth

| PRJNA929992 | ENA

Transcription profiling of human colorectal adenocarcinoma samples transfected with a miR-10a repressor to identify candidate target genes of miR-10a

Project description:MiR-10a inhibits colon cancer invasion and metastasis. To search the candidate target genes of miR-10a, SW480 cells were transfected with miR-10a blockage to suppress miR-10a activity and the differentially expressed genes were detected by cDNA microarray analysis. Some of the up-regulated genes may be candidate target genes of miR-10a.

2009-02-20 | E-MEXP-2061 | biostudies-arrayexpress

Phosphodiesterase 10A inactivation protects against doxorubicin-induced cardiotoxicity and concomitantly inhibits tumor growth

Project description:Phosphodiesterase 10A (PDE10A), by degrading cAMP/cGMP, play critical roles in cardiovascular biology/disease. Cardiotoxicity is a clinical complication of chemotherapy. We aim to determine the role of PDE10A in cancer growth and cardiotoxicity induced by doxorubicin (DOX), a chemotherapy drug. We found that PDE10A deficiency/inhibition alleviated DOX-induced cardiotoxicity in C57Bl/6J mice, including myocardial atrophy, apoptosis, and dysfunction. RNAseq study revealed several PDE10A-regulated signaling associated with DOX-induced cardiotoxicity. In cancer cells, PDE10A inhibition increased the death, decreased the proliferation, and potentiated the effect of DOX in various cancer-cell lines. Importantly, in nude mice with implanted ovarian cancer xenografts, PDE10A inhibition attenuated tumor growth while protected against DOX-induced cardiotoxicity. In isolated cardiomyocytes (CMs), PDE10A contributed to DOX-induced CM death via promoting mitochondrial dysfunction, and to CM atrophy via potentiating foxo3 signaling. Collectively, our study elucidates a novel role for PDE10A in cardiotoxicity and cancer growth in vitro and in vivo, and suggest that PDE10A inhibition may represent a novel strategy in cancer therapy.

2023-06-22 | GSE224157 | GEO

Gene expression profiles MCF-10A cells overexpressing MBD2

2013-06-17 | GSE47873 | GEO

Phosphodiesterase 10A is overexpressed in lung tumor cells and inhibitors selectively suppress growth by blocking ?-catenin and MAPK signaling.

Project description:Phosphodiesterase 10A (PDE10) is a cyclic nucleotide (e.g. cGMP) degrading enzyme highly expressed in the brain striatum where it plays an important role in dopaminergic neurotransmission, but has limited expression and no known physiological function outside the central nervous system. Here we report that PDE10 mRNA and protein levels are strongly elevated in human non-small cell lung cancer cells and lung tumors compared with normal human airway epithelial cells and lung tissue, respectively. Genetic silencing of PDE10 or inhibition by small molecules such as PQ10 was found to selectively inhibit the growth and colony formation of lung tumor cells. PQ10 treatment of lung tumor cells rapidly increased intracellular cGMP levels and activated cGMP-dependent protein kinase (PKG) at concentrations that inhibit lung tumor cell growth. PQ10 also increased the phosphorylation of ?-catenin and reduced its levels, which paralleled the suppression of cyclin D1 and survivin but preceded the activation of PARP and caspase cleavage. PQ10 also suppressed RAS-activated RAF/MAPK signaling within the same concentration range and treatment period as required for cGMP elevation and PKG activation. These results show that PDE10 is overexpressed during lung cancer development and essential for lung tumor cell growth in which inhibitors can selectively induce apoptosis by increasing intracellular cGMP levels and activating PKG to suppress oncogenic ?-catenin and MAPK signaling.

| S-EPMC5642477 | biostudies-literature

Gene expression profiles MCF-10A cells overexpressing MBD2

Project description:Methylated DNA binding protein 2 (MBD2) has been shown to bind specific methylated promoters and suppress transcription. Here we systematically investigate MBD2 suppression by overexpressing MBD2 in MCF-10A cells and generating gene expression profiles of overexpressing cells and normal MCF-10A cells. MCF-10A cells were infected with MBD2 lentivirus in order to increase MBD2 expression. Total RNA was extracted from both infected and non-infected cells and hybridized to Affymetrix gene expression microarrays. Three technical replicates were hybridized for infected and non-infected cells.

2013-06-17 | E-GEOD-47873 | biostudies-arrayexpress

The Wnt/β-catenin and RAS-ERK Pathways were Activated in Tissues of Chemotherapy-Resistant Gastric Cancer PDX Tumor

Project description:Chemotherapy resistance and disease recurrence remains major causes of gastric cancer patient mortality. We describe possible relationship between Wnt/b-catenin and RAS/ERK pathways in GC patients and acquired-resistant GC PDX tumors against FOLFOX, 5-fluorouracil-based chemotherapy. RNA sequencing analysis also demonstrates that Wnt/b-catenin pathway is an actionable target pathway for overcoming the chemotherapy resistance. These provide that an approach targeting both Wnt/b-catenin and RAS/ERK pathways could be novel therapeutic strategy in GC resistant to standard chemotherapy.

2019-05-26 | GSE128967 | GEO

Methylation profiles of MCF-10A cells infected with MBD2 lentivirus

2013-06-13 | GSE47857 | GEO