TY - JOUR

T1 - PP2A-based triple-strike therapy overcomes mitochondrial apoptosis resistance in brain cancer cells

AU - Denisova, Oxana V.

AU - Merisaari, Joni

AU - Huhtaniemi, Riikka

AU - Qiao, Xi

AU - Yetukuri, Laxman

AU - Jumppanen, Mikael

AU - Kaur, Amanpreet

AU - Pääkkönen, Mirva

AU - von Schantz-Fant, Сarina

AU - Ohlmeyer, Michael

AU - Wennerberg, Krister

AU - Kauko, Otto

AU - Koch, Raphael

AU - Aittokallio, Tero

AU - Taipale, Mikko

AU - Westermarck, Jukka

N1 - Publisher Copyright: © 2023 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

PY - 2023

Y1 - 2023

N2 - 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.

AB - 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.

KW - AKT

KW - apoptosis

KW - glioblastoma

KW - mitochondria

KW - PDK

KW - PP2A

U2 - 10.1002/1878-0261.13488

DO - 10.1002/1878-0261.13488

M3 - Journal article

C2 - 37458534

AN - SCOPUS:85165625743

VL - 17

SP - 1803

EP - 1820

JO - Molecular Oncology

JF - Molecular Oncology

SN - 1574-7891

IS - 9

ER -