Targeting Pyruvate Kinase M2 Phosphorylation Reverses Aggressive Cancer Phenotypes
| Autor: | Viswanathan Muthusamy, Brandon M. Gassaway, Jesse Rinehart, David L. Rimm, Maria Apostolidi, Ioannis A. Vathiotis, Patricia Gaule |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Proteomics
Thyroid Hormones Cancer Research Pyruvate Kinase Active Transport Cell Nucleus Pyridinium Compounds Triple Negative Breast Neoplasms PKM2 medicine.disease_cause Article Cyclic N-Oxides Mice chemistry.chemical_compound Cyclin-dependent kinase Cell Line Tumor Neoplasms Biomarkers Tumor medicine Animals Humans Protein Isoforms Neoplasm Invasiveness Pyrroles Phosphorylation Dinaciclib biology Genome Human Kinase Indolizines Membrane Proteins Pyridazines Drug Combinations Phenotype Oncology chemistry Cancer cell MCF-7 Cells biology.protein Cancer research Proteoglycans Collagen Laminin Carrier Proteins Carcinogenesis Oxidation-Reduction Neoplasm Transplantation CDK inhibitor Pyruvate kinase |
| Zdroj: | Cancer Res |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype with low survival rate and a lack of biomarkers and targeted treatments. Here, we target pyruvate kinase M2 (PKM2), a key metabolic component of oncogenesis. In patients with TNBC, PKM2pS37 was identified as a prominent phosphoprotein corresponding to the aggressive breast cancer phenotype that showed a characteristic nuclear staining pattern and prognostic value. Phosphorylation of PKM2 at S37 was connected with a cyclin-dependent kinase (CDK) pathway in TNBC cells. In parallel, pyruvate kinase activator TEPP-46 bound PKM2pS37 and reduced its nuclear localization. In a TNBC mouse xenograft model, treatment with either TEPP-46 or the potent CDK inhibitor dinaciclib reduced tumor growth and diminished PKM2pS37. Combinations of dinaciclib with TEPP-46 reduced cell invasion, impaired redox balance, and triggered cancer cell death. Collectively, these data support an approach to identify PKM2pS37-positive TNBC and target the PKM2 regulatory axis as a potential treatment. Significance: PKM2 phosphorylation marks aggressive breast cancer cell phenotypes and targeting PKM2pS37 could be an effective therapeutic approach for treating triple-negative breast cancer. |
| Databáze: | OpenAIRE |
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