Abstract
Mitochondrial glycolysis and hyperactivity of the phosphatidylinositol 3-kinase–protein kinase B (AKT) pathway are hallmarks of malignant brain tumors. However, kinase inhibitors targeting AKT (AKTi) or the glycolysis master regulator pyruvate dehydrogenase kinase (PDKi) have failed to provide clinical benefits for brain tumor patients. Here, we demonstrate that heterogeneous glioblastoma (GB) and medulloblastoma (MB) cell lines display only cytostatic responses to combined AKT and PDK targeting. Biochemically, the combined AKT and PDK inhibition resulted in the shutdown of both target pathways and priming to mitochondrial apoptosis but failed to induce apoptosis. In contrast, all tested brain tumor cell models were sensitive to a triplet therapy, in which AKT and PDK inhibition was combined with the pharmacological reactivation of protein phosphatase 2A (PP2A) by NZ-8-061 (also known as DT-061), DBK-1154, and DBK-1160. We also provide proof-of-principle evidence for in vivo efficacy in the intracranial GB and MB models by the brain-penetrant triplet therapy (AKTi + PDKi + PP2A reactivator). Mechanistically, PP2A reactivation converted the cytostatic AKTi + PDKi response to cytotoxic apoptosis, through PP2A-elicited shutdown of compensatory mitochondrial oxidative phosphorylation and by increased proton leakage. These results encourage the development of triple-strike strategies targeting mitochondrial metabolism to overcome therapy tolerance in brain tumors.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Molecular Oncology |
| Vol/bind | 17 |
| Udgave nummer | 9 |
| Sider (fra-til) | 1803-1820 |
| Antal sider | 18 |
| ISSN | 1574-7891 |
| DOI | |
| Status | Udgivet - 2023 |
Bibliografisk note
Funding Information:We kindly thank Dr William Leenders (Radboud University Medical Center, the Netherlands) for E98‐Fluc‐mCherry cells, Professor Pirjo Laakkonen (University of Helsinki, Finland) for U87MG and U251MG cell lines, HIFko astrocytes, and patient‐derived GSCs, BT3‐CD133 and BT12, and Professor Johanna Ivaska (Turku Bioscience, Finland) for human fibroblasts and useful comments on the manuscript. Authors acknowledge the Biocenter Finland infrastructure, especially Turku Proteomics Facility, Turku Bioimaging, and Genome Editing Core at Turku Bioscience Centre, Turku Center for Disease Modelling at the University of Turku. Personal acknowledgements to Dr Nikhil Gupta for help with the nucleofection technique; MSc William Eccleshall and MSc Mung Kwan Long for help with Seahorse experiments; Dr Kari Kurppa for expert help with Incucyte experiments and for helpful discussions; Taina Kalevo‐Mattila for excellent technical support, as well as the entire Turku Bioscience personnel for excellent working environment. This work was supported by Sigrid Juselius Foundation (JW), K. Albin Johanssons Foundation (JW), Finnish Cancer Foundation (180157, JW), Finnish Cultural Foundation Central Fund (00160159, OVD), Finnish Cultural Foundation Varsinais‐Suomi Regional Fund (85191366, OVD), AAMU Pediatric Cancer Foundation (201900013, OVD), Turku Doctoral Programme of Molecular Medicine (JM), and Academy of Finland (TA). +
Funding Information:
We kindly thank Dr William Leenders (Radboud University Medical Center, the Netherlands) for E98-Fluc-mCherry cells, Professor Pirjo Laakkonen (University of Helsinki, Finland) for U87MG and U251MG cell lines, HIFko astrocytes, and patient-derived GSCs, BT3-CD133+ and BT12, and Professor Johanna Ivaska (Turku Bioscience, Finland) for human fibroblasts and useful comments on the manuscript. Authors acknowledge the Biocenter Finland infrastructure, especially Turku Proteomics Facility, Turku Bioimaging, and Genome Editing Core at Turku Bioscience Centre, Turku Center for Disease Modelling at the University of Turku. Personal acknowledgements to Dr Nikhil Gupta for help with the nucleofection technique; MSc William Eccleshall and MSc Mung Kwan Long for help with Seahorse experiments; Dr Kari Kurppa for expert help with Incucyte experiments and for helpful discussions; Taina Kalevo-Mattila for excellent technical support, as well as the entire Turku Bioscience personnel for excellent working environment. This work was supported by Sigrid Juselius Foundation (JW), K. Albin Johanssons Foundation (JW), Finnish Cancer Foundation (180157, JW), Finnish Cultural Foundation Central Fund (00160159, OVD), Finnish Cultural Foundation Varsinais-Suomi Regional Fund (85191366, OVD), AAMU Pediatric Cancer Foundation (201900013, OVD), Turku Doctoral Programme of Molecular Medicine (JM), and Academy of Finland (TA).
Publisher Copyright:
© 2023 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.