ArticleClinical cancer research : an official journal of the American Association for Cancer Research2013
Inhibition of protein phosphatase 2A radiosensitizes pancreatic cancers by modulating CDC25C/CDK1 and homologous recombination repair.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 63 papers.
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Who cites it
63 citing papers in PubMed, 102 citations in OpenAlex.
- Endogenous inhibitors of PP2A activate oncogenic and DNA damage response kinases in glioblastoma.Cancer letters · 2026Article
- Phosphatases in tumor cell immune escape: a perspective based on the camouflage, coercion, cytoprotection.Frontiers in cell and developmental biology · 2026Review
- Lactate Activates the HCAR1/β-Arrestin2/PP2A Signaling Axis to Mediate STAT1/2 Dephosphorylation and Drive Osteosarcoma Progression.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Review
- TIPRL1 and its ATM-dependent phosphorylation promote radiotherapy resistance in head and neck cancer.Cellular oncology (Dordrecht, Netherlands) · 2024Article
- The phosphatase inhibitor LB-100 creates neoantigens in colon cancer cells through perturbation of mRNA splicing.EMBO reports · 2024Article
- PPP2R1A silencing suppresses LUAD progression by sensitizing cells to nelfinavir-induced apoptosis and pyroptosis.Cancer cell international · 2024Article
- Altering phosphorylation in cancer through PP2A modifiers.Cancer cell international · 2024Review
- A Small Molecule Inhibitor of Leucine Carboxyl Methyltransferase-1 Inhibits Cancer Cell Survival.Frontiers in drug discovery · 2024Article
- PP2Ac Deficiency Enhances Tumor Immunogenicity by Activating STING-Type I Interferon Signaling in Glioblastoma.Cancer research · 2023Article
- Novel Cellular Functions of ATR for Therapeutic Targeting: Embryogenesis to Tumorigenesis.International journal of molecular sciences · 2023Review
- Molecular Research in Pancreatic Cancer: Small Molecule Inhibitors, Their Mechanistic Pathways and Beyond.Current issues in molecular biology · 2023Review
- Review
- Reciprocal regulation of CIP2A and AR expression in prostate cancer cells.Discover oncology · 2022Article
- TEAD1 Silencing Regulates Cell Proliferation and Resistance to 5-Fluorouracil in Cutaneous Squamous Cell Carcinoma.Clinical, cosmetic and investigational dermatology · 2022Article
- Translation of DNA Damage Response Inhibitors as Chemoradiation Sensitizers From the Laboratory to the Clinic.International journal of radiation oncology, biology, physics · 2021Article
- RBM6 splicing factor promotes homologous recombination repair of double-strand breaks and modulates sensitivity to chemotherapeutic drugs.Nucleic acids research · 2021Article
- Protein Phosphatase 2A as a Therapeutic Target in Small Cell Lung Cancer.Molecular cancer therapeutics · 2021Article
- Review of PP2A Tumor Biology and Antitumor Effects of PP2A Inhibitor LB100 in the Nervous System.Cancers · 2021Review
- Genome-scale mechanistic modeling of signaling pathways made easy: A bioconductor/cytoscape/web server framework for the analysis of omic data.Computational and structural biotechnology journal · 2021Article
3 more citing papers are in PubMed but not listed here.
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Authors and funding
11 authors at 2 institutions in 1 country.
Funding
Abstract
purposeTo identify targets whose inhibition may enhance the efficacy of chemoradiation in pancreatic cancer and thus improve survival, we conducted an siRNA library screen in pancreatic cancer cells. We investigated PPP2R1A, a scaffolding subunit of protein phosphatase 2A (PP2A) as a lead radiosensitizing target. EXPERIMENTAL
designWe determined the effect of PP2A inhibition by genetic (PPP2R1A siRNA) and pharmacologic (LB100, a small molecule entering phase I clinical trials) approaches on radiosensitization of Panc-1 and MiaPaCa-2 pancreatic cancer cells both in vitro and in vivo.
resultsPPP2R1A depletion by siRNA radiosensitized Panc-1 and MiaPaCa-2 cells, with radiation enhancement ratios of 1.4 (P < 0.05). Likewise, LB100 produced similar radiosensitization in pancreatic cancer cells, but minimal radiosensitization in normal small intestinal cells. Mechanistically, PPP2R1A siRNA or LB100 caused aberrant CDK1 activation, likely resulting from accumulation of the active forms of PLK1 (pPLK1 T210) and CDC25C (pCDC25C T130). Furthermore, LB100 inhibited radiation-induced Rad51 focus formation and homologous recombination repair (HRR), ultimately leading to persistent radiation-induced DNA damage, as reflected by γ-H2AX expression. Finally, we identified CDC25C as a key PP2A substrate involved in LB100-mediated radiosensitization as depletion of CDC25C partially reversed LB100-mediated radiosensitization. In a mouse xenograft model of human pancreatic cancer, LB100 produced significant radiosensitization with minimal weight loss.
conclusionsCollectively, our data show that PP2A inhibition radiosensitizes pancreatic cancer both in vitro and in vivo via activation of CDC25C/CDK1 and inhibition of HRR, and provide proof-of-concept evidence that PP2A is a promising target for the improvement of local therapy in pancreatic cancer.
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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.