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

Oxana V. Denisova, Joni Merisaari, Riikka Huhtaniemi, Xi Qiao, Laxman Yetukuri, Mikael Jumppanen, Amanpreet Kaur, Mirva Pääkkönen, Сarina von Schantz-Fant, Michael Ohlmeyer, Krister Wennerberg, Otto Kauko, Raphael Koch, Tero Aittokallio, Mikko Taipale, Jukka Westermarck*

*Corresponding author for this work

Research output: Contribution to journalArticleScientificpeer-review

4 Citations (Scopus)
13 Downloads (Pure)

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.

Original languageEnglish
Pages (from-to)1803-1820
Number of pages18
JournalMolecular Oncology
Volume17
Issue number9
DOIs
Publication statusPublished - Sept 2023
MoE publication typeA1 Journal article-refereed

Keywords

  • AKT
  • apoptosis
  • glioblastoma
  • mitochondria
  • PDK
  • PP2A

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