The Journal of cell biology, 2019-06, Vol.218 (6), p.1943-1957
2019
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Details
- Autor(en) / Beteiligte
- Titel
- The PHLPP2 phosphatase is a druggable driver of prostate cancer progression
- Ist Teil von
- The Journal of cell biology, 2019-06, Vol.218 (6), p.1943-1957
- Ort / Verlag
- United States: Rockefeller University Press
- Erscheinungsjahr
- 2019
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Metastatic prostate cancer commonly presents with targeted, bi-allelic mutations of the and tumor suppressor genes. In contrast, however, most candidate tumor suppressors are part of large recurrent hemizygous deletions, such as the common chromosome 16q deletion, which involves the AKT-suppressing phosphatase PHLPP2. Using RapidCaP, a genetically engineered mouse model of mutant metastatic prostate cancer, we found that complete loss of paradoxically blocks prostate tumor growth and disease progression. Surprisingly, we find that Phlpp2 is essential for supporting Myc, a key driver of lethal prostate cancer. Phlpp2 dephosphorylates threonine-58 of Myc, which renders it a limiting positive regulator of Myc stability. Furthermore, we show that small-molecule inhibitors of PHLPP2 can suppress MYC and kill mutant cells. Our findings reveal that the frequent hemizygous deletions on chromosome 16q present a druggable vulnerability for targeting MYC protein through PHLPP2 phosphatase inhibitors.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0021-9525eISSN: 1540-8140DOI: 10.1083/JCB.201902048Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6548123
- Format
- –
- Schlagworte
- AKT protein, Animals, Cell Proliferation, Chromosome deletion, Chromosomes, Clonal deletion, Disease Progression, Genetic engineering, Humans, Inhibitors, Male, Metastases, Metastasis, Mice, Mice, Knockout, Mutation, Myc protein, Neoplasm Metastasis, p53 Protein, Phosphatase, Phosphoprotein Phosphatases - antagonists & inhibitors, Phosphoprotein Phosphatases - physiology, Phosphorylation, Prostate cancer, Prostatic Neoplasms - drug therapy, Prostatic Neoplasms - genetics, Prostatic Neoplasms - metabolism, Prostatic Neoplasms - pathology, Protein Stability, Proto-Oncogene Proteins c-akt - genetics, Proto-Oncogene Proteins c-akt - metabolism, Proto-Oncogene Proteins c-myc - chemistry, Proto-Oncogene Proteins c-myc - genetics, Proto-Oncogene Proteins c-myc - metabolism, PTEN Phosphohydrolase - physiology, PTEN protein, Signal Transduction, Small Molecule Libraries - pharmacology, Suppressors, Threonine, Tumor Cells, Cultured, Tumor suppressor genes, Tumor Suppressor Protein p53 - physiology, Tumors