ArticleJCI insight2023
Inhibition of phosphodiesterase 4D suppresses mTORC1 signaling and pancreatic cancer growth.
Article in JCI insight, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 11 citations in OpenAlex.
- Post-Translational Modifications in Pancreatic Cancer: Mechanisms to Clinical Applications.Journal of gastroenterology and hepatology · 2026Review
- KTX207-mediated PDE4D degradation disrupts tumour cell migration, invasion, and angiogenic potential.Cell communication and signaling : CCS · 2026Article
- Article
- H3K18la-PSMG1 Axis in Bladder Cancer Progression: Curcumin as a Therapeutic Candidate.International journal of biological sciences · 2026Article
- PDE4C stabilized by ELAVL1 promotes lymph node metastasis in papillary thyroid cancer.American journal of cancer research · 2026Article
- Identification of metabolic driver genes and targeted drug screening for lung adenocarcinoma metastasis at the single-cell resolution.Translational cancer research · 2025Article
- The Integrated Stress Response Pathway Coordinates Translational Control of Multiple Immune Checkpoints in Lung Cancer.Cancer research · 2025Article
- Stress and Obesity Signaling Converge on CREB Phosphorylation to Promote Pancreatic Cancer.Molecular cancer research : MCR · 2025Article
- Targeting protein modification: a new direction for immunotherapy of pancreatic cancer.International journal of biological sciences · 2025Review
- Phosphodiesterases: Evolving Concepts and Implications for Human Therapeutics.Annual review of pharmacology and toxicology · 2025Review
- Lactylated histone H3K18 as a potential biomarker for the diagnosis and prediction of the severity of pancreatic cancer.Clinics (Sao Paulo, Brazil) · 2025Article
- Review
- A prognostic binary classifier comprised of five critical mRNAs stratified pancreatic cancer patients following resection.Heliyon · 2024Article
- Roflumilast inhibits tumor growth and migration in STK11/LKB1 deficient pancreatic cancer.Cell death discovery · 2024Article
- cAMP-PKA/EPAC signaling and cancer: the interplay in tumor microenvironment.Journal of hematology & oncology · 2024Review
- Inflammatory Alterations to Renal Lymphatic Endothelial Cell Gene Expression in Mouse Models of Hypertension.Kidney & blood pressure research · 2024Article
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 1 country.
Funding
Abstract
The mammalian target of rapamycin complex 1 (mTORC1) senses multiple upstream stimuli to orchestrate anabolic and catabolic events that regulate cell growth and metabolism. Hyperactivation of mTORC1 signaling is observed in multiple human diseases; thus, pathways that suppress mTORC1 signaling may help to identify new therapeutic targets. Here, we report that phosphodiesterase 4D (PDE4D) promotes pancreatic cancer tumor growth by increasing mTORC1 signaling. GPCRs paired to Gαs proteins activate adenylyl cyclase, which in turn elevates levels of 3',5'-cyclic adenosine monophosphate (cAMP), whereas PDEs catalyze the hydrolysis of cAMP to 5'-AMP. PDE4D forms a complex with mTORC1 and is required for mTORC1 lysosomal localization and activation. Inhibition of PDE4D and the elevation of cAMP levels block mTORC1 signaling via Raptor phosphorylation. Moreover, pancreatic cancer exhibits an upregulation of PDE4D expression, and high PDE4D levels predict the poor overall survival of patients with pancreatic cancer. Importantly, FDA-approved PDE4 inhibitors repress pancreatic cancer cell tumor growth in vivo by suppressing mTORC1 signaling. Our results identify PDE4D as an important activator of mTORC1 and suggest that targeting PDE4 with FDA-approved inhibitors may be beneficial for the treatment of human diseases with hyperactivated mTORC1 signaling.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.