Preprint
Reciprocal links between methionine metabolism, DNA repair and therapy resistance in glioblastoma
bioRxiv
Cold Spring Harbor Laboratory, 1.1
11/21/2024
DOI: 10.1101/2024.11.20.624542
PMCID: PMC11623687
PMID: 39651281
Abstract
Glioblastoma (GBM) is uniformly lethal due to profound treatment resistance. Altered cellular metabolism is a key mediator of GBM treatment resistance. Uptake of the essential sulfur-containing amino acid methionine is drastically elevated in GBMs compared to normal cells, however, it is not known how this methionine is utilized or whether it relates to GBM treatment resistance.
Here, we find that radiation acutely increases the levels of methionine-related metabolites in a variety of treatment-resistant GBM models. Stable isotope tracing studies further revealed that radiation acutely activates methionine to S-adenosyl methionine (SAM) conversion through an active signaling event mediated by the kinases of the DNA damage response. In vivo tumor SAM synthesis increases after radiation, while normal brain SAM production remains unchanged, indicating a tumor- specific metabolic alteration to radiation. Pharmacological and dietary strategies to block methionine to SAM conversion slowed DNA damage response and increased cell death following radiation in vitro. Mechanistically, these effects are due to depletion of DNA repair proteins and are reversed by SAM supplementation. These effects are selective to GBMs lacking the methionine salvage enzyme methylthioadenosine phosphorylase. Pharmacological inhibition of SAM synthesis hindered tumor growth in flank and orthotopic in vivo GBM models when combined with radiation. By contrast, methionine depletion does not reduce tumor SAM levels and fails to radiosensitize intracranial models, indicating depleting SAM, as opposed to simply lowering methionine, is critical for hindering tumor growth in intracranial models of GBM.
These results highlight a new signaling link between DNA damage and SAM synthesis and define the metabolic fates of methionine in GBM in vivo. Inhibiting radiation-induced SAM synthesis slows DNA repair and augments radiation efficacy in GBM. Using MAT2A inhibitors to deplete SAM may selectively overcome treatment resistance in GBMs with defective methionine salvage while sparing normal brain.
Details
- Title: Subtitle
- Reciprocal links between methionine metabolism, DNA repair and therapy resistance in glioblastoma
- Creators
- Navyateja Korimerla - University of MichiganBaharan Meghdadi - University of MichiganIsra Haq - University of MichiganKari Wilder-Romans - University of MichiganJie Xu - University of MichiganNicole Becker - University of MichiganZiqing Zhu - University of MichiganPeter Kalev - Servier PharmaceuticalsNathan Qi - University of MichiganCharles Evans - University of MichiganMaureen Kachman - University of MichiganZitong Zhao - University of MichiganAngelica Lin - University of MichiganAndrew J Scott - University of MichiganAlexandra O’Brien - University of MichiganAyesha Kothari - University of MichiganPeter Sajjakulnukit - University of MichiganLi Zhang - University of MichiganSravya Palavalasa - University of MichiganErik R Peterson - University of MichiganMarc L Hyer - Servier PharmaceuticalsKatya Marjon - Servier PharmaceuticalsTaryn Sleger - Servier PharmaceuticalsMeredith A Morgan - University of MichiganCostas A Lyssiotis - University of MichiganEverett M. Stone - The University of Texas at AustinSean P. Ferris - University of MichiganTheodore S Lawrence - University of MichiganDeepak Nagrath - University of MichiganWeihua Zhou - University of MichiganDaniel R Wahl - University of Michigan
- Resource Type
- Preprint
- Publication Details
- bioRxiv
- Edition
- 1.1
- DOI
- 10.1101/2024.11.20.624542
- PMID
- 39651281
- PMCID
- PMC11623687
- NLM abbreviation
- bioRxiv
- ISSN
- 2692-8205
- eISSN
- 2692-8205
- Publisher
- Cold Spring Harbor Laboratory
- Number of pages
- 66
- Language
- English
- Date posted
- 11/21/2024
- Academic Unit
- Pathology
- Record Identifier
- 9984966718402771
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