Cooperative treatment effectiveness of ATR and HSP90 inhibition in Ewing’s sarcoma cells

Cell & Bioscience

Felix B. Meyer¹  René Thierbach¹  Doerte Hoelzer²  James F. Beck³  Hauke M. Schadwinkel⁴  Sabine Becker⁴  Marc U. Schaarschmidt⁴  Lisa Marx-Blümel⁴  Jürgen Sonnemann⁵  Martin Westermann⁶  Katrin Buder⁷  Christian Marx⁷  Kanstantsin Siniuk⁷  Melisa Halilovic⁷  Yibo Geng⁸  Zhao-Qi Wang⁹  Joanna Kirkpatrick^1,10 

[1] Department of Human Nutrition, Institute of Nutrition, Friedrich Schiller University Jena, Jena, Germany;Department of Human Nutrition, Institute of Nutrition, Friedrich Schiller University Jena, Jena, Germany;Biopharmaceutical New Technologies (BioNTech) Corporation, Mainz, Germany;Department of Pediatric Hematology and Oncology, Children’s Clinic, Jena University Hospital, Jena, Germany;Department of Pediatric Hematology and Oncology, Children’s Clinic, Jena University Hospital, Jena, Germany;Research Center Lobeda, Jena University Hospital, Jena, Germany;Department of Pediatric Hematology and Oncology, Children’s Clinic, Jena University Hospital, Jena, Germany;Research Center Lobeda, Jena University Hospital, Jena, Germany;Klinik Für Kinder- Und Jugendmedizin, Universitätsklinikum Jena, Am Klinikum 1, 07747, Jena, Germany;Electron Microscopy Center, Jena University Hospital, Jena, Germany;Leibniz Institute On Aging - Fritz Lipmann Institute (FLI), Jena, Germany;Leibniz Institute On Aging - Fritz Lipmann Institute (FLI), Jena, Germany;Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China;Leibniz Institute On Aging - Fritz Lipmann Institute (FLI), Jena, Germany;Faculty of Biology and Pharmacy, Friedrich Schiller University of Jena, Jena, Germany;Leibniz Institute On Aging - Fritz Lipmann Institute (FLI), Jena, Germany;Francis Crick Institute, London, UK;

关键词: ATM;    ATR;    Ewing's sarcoma;    HSP90;    Endoplasmic reticulum (ER) stress;    Apoptosis;   

DOI  :  10.1186/s13578-021-00571-y

来源: Springer

【 摘 要 】

IntroductionEwing's sarcoma is an aggressive childhood malignancy whose outcome has not substantially improved over the last two decades. In this study, combination treatments of the HSP90 inhibitor AUY922 with either the ATR inhibitor VE821 or the ATM inhibitor KU55933 were investigated for their effectiveness in Ewing's sarcoma cells.MethodsEffects were determined in p53 wild-type and p53 null Ewing's sarcoma cell lines by flow cytometric analyses of cell death, mitochondrial depolarization and cell-cycle distribution as well as fluorescence and transmission electron microscopy. They were molecularly characterized by gene and protein expression profiling, and by quantitative whole proteome analysis.ResultsAUY922 alone induced DNA damage, apoptosis and ER stress, while reducing the abundance of DNA repair proteins. The combination of AUY922 with VE821 led to strong apoptosis induction independent of the cellular p53 status, yet based on different molecular mechanisms. p53 wild-type cells activated pro-apoptotic gene transcription and underwent mitochondria-mediated apoptosis, while p53 null cells accumulated higher levels of DNA damage, ER stress and autophagy, eventually leading to apoptosis. Impaired PI3K/AKT/mTOR signaling further contributed to the antineoplastic combination effects of AUY922 and VE821. In contrast, the combination of AUY922 with KU55933 did not produce a cooperative effect.ConclusionOur study reveals that HSP90 and ATR inhibitor combination treatment may be an effective therapeutic approach for Ewing's sarcoma irrespective of the p53 status.

【 授权许可】

CC BY