ArticleMolecular cancer2012
Inhibition of phosphodiesterase-4 (PDE4) activity triggers luminal apoptosis and AKT dephosphorylation in a 3-D colonic-crypt model.
Article in Molecular cancer, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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27 citing papers in PubMed, 51 citations in OpenAlex.
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- ALDH2 regulates oxaliplatin sensitivity via PDE4B in p53-mutant colorectal cancer.International journal of medical sciences · 2026Article
- Targeting neutrophils for cancer therapy.Nature reviews. Drug discovery · 2025Review
- Targeting Phosphodiesterase 4 in Gastrointestinal and Liver Diseases: From Isoform-Specific Mechanisms to Precision Therapeutics.Biomedicines · 2025Review
- The multifaceted role of phosphodiesterase 4 in tumor: from tumorigenesis to immunotherapy.Frontiers in immunology · 2025Review
- PDE10A as a novel diagnostic and therapeutic target in cancer: insights and challenges.Frontiers in oncology · 2025Review
- PDE4D drives rewiring of the MAPK pathway in BRAF-mutated melanoma resistant to MAPK inhibitors.Cell communication and signaling : CCS · 2024Article
- PDE4B promotes the progression of gastric cancer via the PI3K/AKT/MYC pathway and immune infiltration.American journal of cancer research · 2024Article
- Targeting fat mass and obesity-associated protein mitigates human colorectal cancer growthFrontiers in oncology · 2023Article
- Classical epithelial-mesenchymal transition (EMT) and alternative cell death process-driven blebbishield metastatic-witch (BMW) pathways to cancer metastasis.Signal transduction and targeted therapy · 2022Review
- Effects ofMicroorganisms · 2021Article
- Whole-exome sequencing identifies somatic mutations and intratumor heterogeneity in inflammatory breast cancer.NPJ breast cancer · 2021Article
- Potential Cancer- and Alzheimer's Disease-Targeting Phosphodiesterase Inhibitors fromACS omega · 2021Article
- Synthesis, antitumor activity, and molecular docking study of 2-cyclopentyloxyanisole derivatives: mechanistic study of enzyme inhibition.Journal of enzyme inhibition and medicinal chemistry · 2020Article
- Article
- Gene-environment interaction with smoking for increased non-muscle-invasive bladder cancer tumor size.Translational andrology and urology · 2020Article
- PDE4 subtypes in cancer.Oncogene · 2020Review
- Therapeutic Potential of Triptolide as an Anti-Inflammatory Agent in Dextran Sulfate Sodium-Induced Murine Experimental Colitis.Frontiers in immunology · 2020Article
- Inhibition of phosphodiesterase 4D decreases the malignant properties of DLD-1 colorectal cancer cells by repressing the AKT/mTOR/Myc signaling pathway.Oncology letters · 2019Article
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Authors and funding
13 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundWe previously established a three-dimensional (3-D) colonic crypt model using HKe3 cells which are human colorectal cancer (CRC) HCT116 cells with a disruption in oncogenic KRAS, and revealed the crucial roles of oncogenic KRAS both in inhibition of apoptosis and in disruption of cell polarity; however, the molecular mechanism of KRAS-induced these 3-D specific biological changes remains to be elucidated.
resultsAmong the genes that were upregulated by oncogenic KRAS in this model, we focused on the phosphodiesterase 4B (PDE4B) of which expression levels were found to be higher in clinical tumor samples from CRC patients in comparison to those from healthy control in the public datasets of gene expression analysis. PDE4B2 was specifically overexpressed among other PDE4 isoforms, and re-expression of oncogenic KRAS in HKe3 cells resulted in PDE4B overexpression. Furthermore, the inhibition of PDE4 catalytic activity using rolipram reverted the disorganization of HCT116 cells into the normal physiologic state of the epithelial cell polarity by inducing the apical assembly of ZO-1 (a tight junction marker) and E-cadherin (an adherens junction marker) and by increasing the activity of caspase-3 (an apoptosis marker) in luminal cavities. Notably, rolipram reduced the AKT phosphorylation, which is known to be associated with the disruption of luminal cavity formation and CRC development. Similar results were also obtained using PDE4B2-shRNAs. In addition, increased expression of PDE4B mRNA was found to be correlated with relapsed CRC in a public datasets of gene expression analysis.
conclusionsThese results collectively suggested that PDE4B is upregulated by oncogenic KRAS, and also that the inhibition of PDE4 catalytic activity can induce both epithelial cell polarity and luminal apoptosis in CRC, thus highlighting the utility of our 3-D culture (3 DC) model for the KRAS-induced development of CRC in 3-D microenvironment. Indeed, using this model, we found that PDE4B is a promising candidate for a therapeutic target as well as prognostic molecular marker in CRC. Further elucidation of the signaling network of PDE4B2 in 3 DC would provide a better understanding of CRC in vivo.
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