PP2A‐based triple‐strike therapy overcomes mitochondrial apoptosis resistance in brain cancer cells
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 clini...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2023-09-01
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| Series: | Molecular Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/1878-0261.13488 |
| _version_ | 1827822774297559040 |
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| author | Oxana V. Denisova Joni Merisaari Riikka Huhtaniemi Xi Qiao Laxman Yetukuri Mikael Jumppanen Amanpreet Kaur Mirva Pääkkönen Сarina vonSchantz‐Fant Michael Ohlmeyer Krister Wennerberg Otto Kauko Raphael Koch Tero Aittokallio Mikko Taipale Jukka Westermarck |
| author_facet | Oxana V. Denisova Joni Merisaari Riikka Huhtaniemi Xi Qiao Laxman Yetukuri Mikael Jumppanen Amanpreet Kaur Mirva Pääkkönen Сarina vonSchantz‐Fant Michael Ohlmeyer Krister Wennerberg Otto Kauko Raphael Koch Tero Aittokallio Mikko Taipale Jukka Westermarck |
| author_sort | Oxana V. Denisova |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T02:02:25Z |
| format | Article |
| id | doaj.art-a2e1d31113f04fc1a661ea35069e7372 |
| institution | Directory Open Access Journal |
| issn | 1574-7891 1878-0261 |
| language | English |
| last_indexed | 2024-03-12T02:02:25Z |
| publishDate | 2023-09-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj.art-a2e1d31113f04fc1a661ea35069e73722023-09-07T10:57:03ZengWileyMolecular Oncology1574-78911878-02612023-09-011791803182010.1002/1878-0261.13488PP2A‐based triple‐strike therapy overcomes mitochondrial apoptosis resistance in brain cancer cellsOxana V. Denisova0Joni Merisaari1Riikka Huhtaniemi2Xi Qiao3Laxman Yetukuri4Mikael Jumppanen5Amanpreet Kaur6Mirva Pääkkönen7Сarina vonSchantz‐Fant8Michael Ohlmeyer9Krister Wennerberg10Otto Kauko11Raphael Koch12Tero Aittokallio13Mikko Taipale14Jukka Westermarck15Turku Bioscience Centre University of Turku and Åbo Akademi University FinlandTurku Bioscience Centre University of Turku and Åbo Akademi University FinlandTurku Bioscience Centre University of Turku and Åbo Akademi University FinlandTurku Bioscience Centre University of Turku and Åbo Akademi University FinlandTurku Bioscience Centre University of Turku and Åbo Akademi University FinlandTurku Bioscience Centre University of Turku and Åbo Akademi University FinlandTurku Bioscience Centre University of Turku and Åbo Akademi University FinlandTurku Bioscience Centre University of Turku and Åbo Akademi University FinlandInstitute for Molecular Medicine Finland (FIMM), HiLIFE University of Helsinki FinlandIcahn School of Medicine at Mount Sinai New York NY USAInstitute for Molecular Medicine Finland (FIMM), HiLIFE University of Helsinki FinlandTurku Bioscience Centre University of Turku and Åbo Akademi University FinlandUniversity Medical Center Göttingen GermanyInstitute for Molecular Medicine Finland (FIMM), HiLIFE University of Helsinki FinlandDonnelly Centre for Cellular and Biomolecular Research University of Toronto CanadaTurku Bioscience Centre University of Turku and Åbo Akademi University FinlandMitochondrial 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.https://doi.org/10.1002/1878-0261.13488AKTapoptosisglioblastomamitochondriaPDKPP2A |
| spellingShingle | Oxana V. Denisova Joni Merisaari Riikka Huhtaniemi Xi Qiao Laxman Yetukuri Mikael Jumppanen Amanpreet Kaur Mirva Pääkkönen Сarina vonSchantz‐Fant Michael Ohlmeyer Krister Wennerberg Otto Kauko Raphael Koch Tero Aittokallio Mikko Taipale Jukka Westermarck PP2A‐based triple‐strike therapy overcomes mitochondrial apoptosis resistance in brain cancer cells Molecular Oncology AKT apoptosis glioblastoma mitochondria PDK PP2A |
| title | PP2A‐based triple‐strike therapy overcomes mitochondrial apoptosis resistance in brain cancer cells |
| title_full | PP2A‐based triple‐strike therapy overcomes mitochondrial apoptosis resistance in brain cancer cells |
| title_fullStr | PP2A‐based triple‐strike therapy overcomes mitochondrial apoptosis resistance in brain cancer cells |
| title_full_unstemmed | PP2A‐based triple‐strike therapy overcomes mitochondrial apoptosis resistance in brain cancer cells |
| title_short | PP2A‐based triple‐strike therapy overcomes mitochondrial apoptosis resistance in brain cancer cells |
| title_sort | pp2a based triple strike therapy overcomes mitochondrial apoptosis resistance in brain cancer cells |
| topic | AKT apoptosis glioblastoma mitochondria PDK PP2A |
| url | https://doi.org/10.1002/1878-0261.13488 |
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