2. Academic Validation
  3. PKM2 rewires glucose metabolism during radiation therapy to promote an antioxidant response and glioblastoma radioresistance

PKM2 rewires glucose metabolism during radiation therapy to promote an antioxidant response and glioblastoma radioresistance

  • Neuro Oncol. 2023 Jun 5;noad103. doi: 10.1093/neuonc/noad103.
Justine Bailleul 1,  Yangjingyi Ruan 1,  Lobna Abdulrahman 1,  Andrew J Scott 2 3,  Taha Yazal 1,  David Sung 1,  Keunseok Park 4,  Hanna Hoang 1,  Juan Nathaniel 1,  Fang-I Chu 1,  Daisy Palomera 1,  Anahita Sehgal 1,  Jonathan E Tsang 5,  David A Nathanson 5,  Shili Xu 6 5 7,  Junyoung O Park 4,  Johanna Ten Hoeve 5,  Kruttika Bhat 1,  Nathan Qi 8,  Harley I Kornblum 6 9,  Dorthe Schaue 1,  William H McBride 1,  Costas A Lyssiotis 8 3,  Daniel R Wahl 2 3,  Erina Vlashi 1 6
Affiliations

Affiliations

  • 1 Department of Radiation Oncology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.
  • 2 Department of Radiation Oncology, University of Michigan, Ann Arbor, MI.
  • 3 Rogel Cancer Center, University of Michigan, Ann Arbor, MI.
  • 4 Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, CA.
  • 5 Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA.
  • 6 Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA.
  • 7 Crump Institute for Molecular Imaging, David Geffen School of Medicine, UCLA, Los Angeles, CA.
  • 8 Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI.
  • 9 Neuropsychiatric Institute-Semel Institute for Neuroscience & Human Behavior, University of California, Los Angeles, CA.
PMID: 37279645 DOI: 10.1093/neuonc/noad103
Abstract

Background: Resistance to existing therapies is a significant challenge in improving outcomes for glioblastoma (GBM) patients. Metabolic plasticity has emerged as an important contributor to therapy resistance, including radiation therapy (RT). Here, we investigated how GBM cells reprogram their glucose metabolism in response to RT to promote radiation resistance.

Methods: Effects of radiation on glucose metabolism of human GBM specimens were examined in vitro and in vivo with the use of metabolic and enzymatic assays, targeted metabolomics, and FDG-PET. Radiosensitization potential of interfering with PKM2 activity was tested via gliomasphere formation assays and in vivo human GBM models.

Results: Here, we show that RT induces increased glucose utilization by GBM cells, and this is accompanied with translocation of GLUT3 transporters to the cell membrane. Irradiated GBM cells route glucose carbons through the pentose phosphate pathway (PPP) to harness the antioxidant power of the PPP and support survival after radiation. This response is regulated in part by the M2 isoform of Pyruvate Kinase (PKM2). Activators of PKM2 can antagonize the radiation-induced rewiring of glucose metabolism and radiosensitize GBM cells in vitro and in vivo.

Conclusions: These findings open the possibility that interventions designed to target cancer-specific regulators of metabolic plasticity, such as PKM2, rather than specific metabolic pathways, have the potential to improve the radiotherapeutic outcomes in GBM patients.

Keywords

Glioblastoma; PPP; metabolism; plasticity; radiation resistance.

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