ArticleThe Journal of clinical investigation2021
WWP1 inactivation enhances efficacy of PI3K inhibitors while suppressing their toxicities in breast cancer models.
Article in The Journal of clinical investigation, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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The trial behind it
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Who cites it
23 citing papers in PubMed, 21 citations in OpenAlex.
- Secretory Carrier Membrane Protein 3 Knockdown Attenuates Hypoxic Pulmonary Hypertension Potentially Involving WW Domain-Containing E3 Ubiquitin Protein Ligase 1.Biochemical genetics · 2026Article
- E2F-mediated activation of mTORC1 through the ubiquitin-proteasome system promotes lung adenocarcinoma progression.Cell death & disease · 2026Article
- Epigenetic silencing of MSTN via m6A modification underlies the renoprotective effects of engineered MSC exosomes with RBM15 depletion in diabetic nephropathy.Functional & integrative genomics · 2025Article
- FTO activates PD-L1 promotes immunosuppression in breast cancer via the m6A/YTHDF3/PDK1 axis under hypoxic conditions.Journal of advanced research · 2025Article
- Identification and validation of the cellular senescence-associated molecular pattern and diagnostic markers for osteoporosis.BMC medical genomics · 2025Article
- The WWP1-JARID1B axis sustains acute myeloid leukemia chemoresistance.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- [WW domain-containing ubiquitin E3 ligase 1 regulates immune infiltration in tumor microenvironment of ovarian cancer].Nan fang yi ke da xue xue bao = Journal of Southern Medical University · 2025Article
- WWP1 inhibition suppresses the proliferation of pancreatic cancer cells by regulating the PI3K-AKT pathway.Journal of gastroenterology · 2025Article
- GluOC Induced SLC7A11 and SLC38A1 to Activate Redox Processes and Resist Ferroptosis in TNBC.Cancers · 2025Article
- Positive Selection Shapes Breast Cancer Tumor Suppressor Genes: Unveiling Insights into BRCA1, BRCA2, and MDC1 Stability.Journal of molecular evolution · 2025Article
- Role and therapeutic potential of the NEDD4 family in breast cancer.Frontiers in pharmacology · 2025Review
- WWP1 targeting PTEN for polyubiquitination to promote bone metastasis of luminal breast cancer.Scientific reports · 2024Article
- The Senolytic Effect of Indole-3-Carbinol (I3C) on Mouse Embryonic (MEF) and Human Fibroblast Cell Lines.International journal of molecular sciences · 2024Article
- WWP1 inhibition increases SHP2 inhibitor efficacy in colorectal cancer.NPJ precision oncology · 2024Article
- DNMT1-targeting remodeling global DNA hypomethylation for enhanced tumor suppression and circumvented toxicity in oral squamous cell carcinoma.Molecular cancer · 2024Article
- Molecular mechanism of WWP1-mediated ubiquitination modification affecting proliferation and invasion/migration of liver cancer cells.The Kaohsiung journal of medical sciences · 2024Article
- Post-Translational Modification of PTEN Protein: Quantity and Activity.Oncology reviews · 2024Review
- Portrait of WWP1: the current state in human cancer.Frontiers in cell and developmental biology · 2024Review
- WWP1 E3 ligase at the crossroads of health and disease.Cell death & disease · 2023Review
- Synthetic Methodologies and Therapeutic Potential of Indole-3-Carbinol (I3C) and Its Derivatives.Pharmaceuticals (Basel, Switzerland) · 2023Review
Corrections and comments
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Authors and funding
17 authors at 4 institutions in 5 countries.
Funding
Abstract
Activation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway is a pervasive event in tumorigenesis due to PI3K mutation and dysfunction of phosphatase and tensin homolog deleted on chromosome 10 (PTEN). Pharmacological inhibition of PI3K has resulted in variable clinical outcomes, however, raising questions regarding the possible mechanisms of unresponsiveness and resistance to treatment. WWP1 is an oncogenic HECT-type ubiquitin E3 ligase frequently amplified and mutated in multiple cancers, as well as in the germ lines of patients predisposed to cancer, and was recently found to activate PI3K signaling through PTEN inactivation. Here, we demonstrate that PTEN dissociated from the plasma membrane upon treatment with PI3K inhibitors through WWP1 activation, whereas WWP1 genetic or pharmacological inhibition restored PTEN membrane localization, synergizing with PI3K inhibitors to suppress tumor growth both in vitro and in vivo. Furthermore, we demonstrate that WWP1 inhibition attenuated hyperglycemia and the consequent insulin feedback, which is a major tumor-promoting side effect of PI3K inhibitors. Mechanistically, we found that AMPKα2 was ubiquitinated and, in turn, inhibited in its activatory phosphorylation by WWP1, whereas WWP1 inhibition facilitated AMPKα2 activity in the muscle to compensate for the reduction in glucose uptake observed upon PI3K inhibition. Thus, our identification of the cell-autonomous and systemic roles of WWP1 inhibition expands the therapeutic potential of PI3K inhibitors and reveals new avenues of combination cancer therapy.
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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.