@article{e6322a7e72fb42398410f8adf409298a,
title = "Mitochondrial ClpP-Mediated Proteolysis Induces Selective Cancer Cell Lethality",
abstract = "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.",
keywords = "acute myeloid leukemia, cancer, imipridone, lymphoma, mitochondrial ClpP, mitochondrial proteolysis, oxidative phosphorylation, respiratory chain complex",
author = "Jo Ishizawa and Zarabi, {Sarah F.} and Davis, {R. Eric} and Ondrej Halgas and Takenobu Nii and Yulia Jitkova and Ran Zhao and Jonathan St-Germain and Heese, {Lauren E.} and Grace Egan and Ruvolo, {Vivian R.} and Barghout, {Samir H.} and Yuki Nishida and Rose Hurren and Wencai Ma and Marcela Gronda and Todd Link and Keith Wong and Mark Mabanglo and Kensuke Kojima and Gautam Borthakur and Neil MacLean and Ma, {Man Chun John} and Leber, {Andrew B.} and Minden, {Mark D.} and Walid Houry and Hagop Kantarjian and Martin Stogniew and Brian Raught and Pai, {Emil F.} and Schimmer, {Aaron D.} and Michael Andreeff",
note = "Funding Information: We thank Ronald A. DePinho for reviewing the manuscript; Rodrigo Jacamo, Teresa McQueen, and Venkata Lokesh Battula for support in establishing some of the engineered cell lines; Xiaoming Wang, Hong Mu, Huaxian Ma, Bing Carter, Qi Zhang, Lina Han, and Marina Konopleva for assisting in in vivo studies; Jairo Matthews, Gheath Al-Atrash, and Steven Kornblau for primary sample and data collection, Wolfgang Oster at Oncoceutics for providing imipridones, and Shaun Labiuk, Canadian Light Source, for diffraction data collection. Part of the experiments were performed at the Sequencing and Microarray Facility, High Resolution Electron Microscopy Facility, and Flow Cytometry and Cellular Imaging Facility at MD Anderson, supported by CCSG grant NIH P30CA016672. This work was supported by the Canada Research Chairs program (to E.F.P.), Leukemia and Lymphoma Society, Canadian Institutes of Health Research, MaRS Innovation, the Ontario Institute for Cancer Research with funding provided by the Ontario Ministry of Research and Innovation, the Princess Margaret Cancer Centre Foundation, and the Ministry of Long Term Health and Planning in the Province of Ontario, the Barbara Baker Chair in Leukemia and Related Diseases (to A.D.S.); Haas Chair in Genetics, NIH Leukemia SPORE grant P50CA100632 and the University of Texas MD Anderson Cancer Center Support Grant CA016672, MDS/AML Moon Shot (to M.A.); and NIH Leukemia SPORE Career Enhancement Programs (to J.I.). J.I. S.F.Z. A.D.S. and M.A. designed the study, analyzed results, and wrote the manuscript. R.E.D. W.M. and J.M.C.M. analyzed RNA-seq data. O.H. and E.F.P. designed and performed crystallography, modeling, ITC, gel filtration experiments and analyzed results and wrote the manuscript. J.S.T. analyzed the data and wrote the manuscript. R.Z. Y.J. L.E.H. J.S.T. V.R.R. T.N. G.E. S.H.B. Y.N. R.H. M.G. K.W. M.M. K.K. N.M. and A.B.L. performed the experiments and analyzed the data. T.L. G.B. and H.K. did study design, data analysis, and interpretation. M.D.M. provided critical reagents and supervised research. W.H. and B.R. supervised research and wrote the manuscript. M.S. designed the ONC212 chemical structure. R.E.D. and O.H. contributed equally to the study. M.S. is an employee and stockholder of Oncoceutics. M.A. serves on the scientific advisory board and is a stockholder of Oncoceutics. A.D.S. has received consulting fees from Novartis, Jazz and Otsuka Pharmaceuticals, and research grants from Medivir and Takeda Pharmaceuticals, and holds stock in Abbvie, Adamas Pharmaceuticals, Insmed, Myovant Sciences, Theravance Biopharma. We have filed invention disclosure forms related to the use of ONC201 in AML with high ClpP expression. Funding Information: We thank Ronald A. DePinho for reviewing the manuscript; Rodrigo Jacamo, Teresa McQueen, and Venkata Lokesh Battula for support in establishing some of the engineered cell lines; Xiaoming Wang, Hong Mu, Huaxian Ma, Bing Carter, Qi Zhang, Lina Han, and Marina Konopleva for assisting in in vivo studies; Jairo Matthews, Gheath Al-Atrash, and Steven Kornblau for primary sample and data collection, Wolfgang Oster at Oncoceutics for providing imipridones, and Shaun Labiuk, Canadian Light Source, for diffraction data collection. Part of the experiments were performed at the Sequencing and Microarray Facility, High Resolution Electron Microscopy Facility, and Flow Cytometry and Cellular Imaging Facility at MD Anderson, supported by CCSG grant NIH P30CA016672 . This work was supported by the Canada Research Chairs program (to E.F.P.), Leukemia and Lymphoma Society , Canadian Institutes of Health Research , MaRS Innovation , the Ontario Institute for Cancer Research with funding provided by the Ontario Ministry of Research and Innovation , the Princess Margaret Cancer Centre Foundation , and the Ministry of Long Term Health and Planning in the Province of Ontario, the Barbara Baker Chair in Leukemia and Related Diseases (to A.D.S.); Haas Chair in Genetics, NIH Leukemia SPORE grant P50CA100632 and the University of Texas MD Anderson Cancer Center Support Grant CA016672 , MDS/AML Moon Shot (to M.A.); and NIH Leukemia SPORE Career Enhancement Programs (to J.I.). Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",
year = "2019",
month = may,
day = "13",
doi = "10.1016/j.ccell.2019.03.014",
language = "English (US)",
volume = "35",
pages = "721--737.e9",
journal = "Cancer cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "5",
}