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Mutant IDH1 gliomas downregulate phosphocholine and phosphoethanolamine synthesis in a 2-hydroxyglutarate-dependent manner
- Source :
- Repisalud, Instituto de Salud Carlos III (ISCIII), Cancer & Metabolism, Vol 6, Iss 1, Pp 1-13 (2018), Cancer & metabolism, vol 6, iss 1, Cancer & Metabolism
- Publication Year :
- 2018
- Publisher :
- BMC, 2018.
-
Abstract
- Background: Magnetic resonance spectroscopy (MRS) studies have identified elevated levels of the phospholipid precursor phosphocholine (PC) and phosphoethanolamine (PE) as metabolic hallmarks of cancer. Unusually, however, PC and PE levels are reduced in mutant isocitrate dehydrogenase 1 (IDHmut) gliomas that produce the oncometabolite 2-hydroxyglutarate (2-HG) relative to wild-type IDH1 (IDHwt) gliomas. The goal of this study was to determine the molecular mechanism underlying this unusual metabolic reprogramming in IDHmut gliomas. Methods: Steady-state PC and PE were quantified using 31P-MRS. To quantify de novo PC and PE synthesis, we used 13C-MRS and measured flux to 13C-PC and 13C-PE in cells incubated with [1,2-13C]-choline and [1,2-13C]-ethanolamine. The activities of choline kinase (CK) and ethanolamine kinase (EK), the enzymes responsible for PC and PE synthesis, were quantified using 31P-MR-based assays. To interrogate the role of 2-HG, we examined IDHwt cells incubated with 2-HG and, conversely, IDHmut cells treated with the IDHmut inhibitor AGI-5198. To examine the role of hypoxia-inducible factor 1-α (HIF-1α), we silenced HIF-1α using RNA interference. To confirm our findings in vivo and in the clinic, we studied IDHwt and IDHmut orthotopic tumor xenografts and glioma patient biopsies. Results: De novo synthesis of PC and PE was reduced in IDHmut cells relative to IDHwt. Concomitantly, CK activity and EK activity were reduced in IDHmut cells. Pharmacological manipulation of 2-HG levels established that 2-HG was responsible for reduced CK activity, EK activity, PC and PE. 2-HG has previously been reported to stabilize levels of HIF-1α, a known regulator of CK activity. Silencing HIF-1α in IDHmut cells restored CK activity, EK activity, PC and PE to IDHwt levels. Our findings were recapitulated in IDHmut orthotopic tumor xenografts and, most importantly, in IDHmut patient biopsies, validating our findings in vivo and in the clinic. Conclusions: This study identifies, to our knowledge for the first time, a direct role for 2-HG in the downregulation of CK and EK activity, and thereby, PC and PE synthesis in IDHmut gliomas. These results highlight the unusual reprogramming of phospholipid metabolism in IDHmut gliomas and have implications for the identification of MRS-detectable metabolic biomarkers associated with 2-HG status. This work was supported by the following grants: NIH R01CA172845 (SMR), NIH R01CA197254 (SMR), NIH R01CA154915 (SMR), FP7/2007-2013 REA600396 (JLI), SAF2014-59118-JIN (JLI), UCSF Brain Tumor Loglio Collective (SMR, ROP, JJP), NICO (SMR), UCSF Brain Tumor Research Center SPORE Tissue Core (P50CA97257) and UCSF Brain Tumor Research Center SPORE Career Development Grant (P50CA97257 to PV). Sí
- Subjects :
- 0301 basic medicine
Choline kinase
IDH1
HIF-1α
lcsh:RC254-282
Brain tumors
IDH1 mutation
03 medical and health sciences
chemistry.chemical_compound
Rare Diseases
Downregulation and upregulation
In vivo
Clinical Research
Glioma
Magnetic resonance spectroscopy
medicine
Phosphoethanolamine
Phosphocholine
Cancer
Ethanolamine kinase
Chemistry
Research
HIF-1 alpha
Metabolic reprogramming
medicine.disease
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
2-Hydroxyglutarate
Molecular biology
3. Good health
Brain Disorders
Brain Cancer
Psychiatry and Mental health
030104 developmental biology
Isocitrate dehydrogenase
Biotechnology
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Repisalud, Instituto de Salud Carlos III (ISCIII), Cancer & Metabolism, Vol 6, Iss 1, Pp 1-13 (2018), Cancer & metabolism, vol 6, iss 1, Cancer & Metabolism
- Accession number :
- edsair.doi.dedup.....7f01b67c52d32e7ab32995055a2071c7