Cancer cell, 2019-05, Vol.35 (5), p.721-737.e9
- Ishizawa, Jo
- Zarabi, Sarah F.
- Davis, R. Eric
- Halgas, Ondrej
- Nii, Takenobu
- Jitkova, Yulia
- Zhao, Ran
- St-Germain, Jonathan
- Heese, Lauren E.
- Egan, Grace
- Ruvolo, Vivian R.
- Barghout, Samir H.
- Nishida, Yuki
- Hurren, Rose
- Ma, Wencai
- Gronda, Marcela
- Link, Todd
- Wong, Keith
- Mabanglo, Mark
- Kojima, Kensuke
- Borthakur, Gautam
- MacLean, Neil
- Ma, Man Chun John
- Leber, Andrew B.
- Minden, Mark D.
- Houry, Walid
- Kantarjian, Hagop
- Stogniew, Martin
- Raught, Brian
- Pai, Emil F.
- Schimmer, Aaron D.
- Andreeff, Michael
2019
Volltextzugriff (PDF)
Details
- Autor(en) / Beteiligte
- Ishizawa, Jo
- Zarabi, Sarah F.
- Davis, R. Eric
- Halgas, Ondrej
- Nii, Takenobu
- Jitkova, Yulia
- Zhao, Ran
- St-Germain, Jonathan
- Heese, Lauren E.
- Egan, Grace
- Ruvolo, Vivian R.
- Barghout, Samir H.
- Nishida, Yuki
- Hurren, Rose
- Ma, Wencai
- Gronda, Marcela
- Link, Todd
- Wong, Keith
- Mabanglo, Mark
- Kojima, Kensuke
- Borthakur, Gautam
- MacLean, Neil
- Ma, Man Chun John
- Leber, Andrew B.
- Minden, Mark D.
- Houry, Walid
- Kantarjian, Hagop
- Stogniew, Martin
- Raught, Brian
- Pai, Emil F.
- Schimmer, Aaron D.
- Andreeff, Michael
- Titel
- Mitochondrial ClpP-Mediated Proteolysis Induces Selective Cancer Cell Lethality
- Ist Teil von
- Cancer cell, 2019-05, Vol.35 (5), p.721-737.e9
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2019
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- The mitochondrial caseinolytic protease P (ClpP) plays a central role in mitochondrial protein quality control by degrading misfolded proteins. Using genetic and chemical approaches, we showed that hyperactivation of the protease selectively kills cancer cells, independently of p53 status, by selective degradation of its respiratory chain protein substrates and disrupts mitochondrial structure and function, while it does not affect non-malignant cells. We identified imipridones as potent activators of ClpP. Through biochemical studies and crystallography, we show that imipridones bind ClpP non-covalently and induce proteolysis by diverse structural changes. Imipridones are presently in clinical trials. Our findings suggest a general concept of inducing cancer cell lethality through activation of mitochondrial proteolysis. •Activation of the mitochondrial ClpP induces p53-independent cancer cell lethality•Imipridones are allosteric agonists of ClpP, being tested in human clinical trials•ClpP activation increases proteolysis of mitochondrial proteins•ClpP-mediated mitochondrial proteolysis impairs mitochondrial respiratory function Ishizawa et al. report that hyperactivating the mitochondrial caseinolytic protease P (ClpP) degrades respiratory chain proteins, disrupts mitochondrial function, and selectively kills cancer cells, regardless of p53 status. They identify imipridones as hyperactivators of ClpP and show their anti-tumor activity.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1535-6108eISSN: 1878-3686DOI: 10.1016/j.ccell.2019.03.014Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6620028
- Format
- –
- Schlagworte
- acute myeloid leukemia, Animals, cancer, Cell Line, Tumor, Cell Survival - drug effects, Crystallography, X-Ray, Drug Screening Assays, Antitumor, Endopeptidase Clp - chemistry, Endopeptidase Clp - genetics, Endopeptidase Clp - metabolism, Female, HCT116 Cells, HEK293 Cells, Heterocyclic Compounds, 4 or More Rings - administration & dosage, Heterocyclic Compounds, 4 or More Rings - chemistry, Heterocyclic Compounds, 4 or More Rings - pharmacology, Humans, imipridone, Leukemia, Myeloid, Acute - drug therapy, Leukemia, Myeloid, Acute - genetics, Leukemia, Myeloid, Acute - metabolism, lymphoma, Mice, Mitochondria - metabolism, mitochondrial ClpP, mitochondrial proteolysis, Models, Molecular, oxidative phosphorylation, Point Mutation, Protein Conformation - drug effects, Proteolysis, respiratory chain complex, Tumor Suppressor Protein p53 - metabolism, Xenograft Model Antitumor Assays