title: Mutant IDH1 expression is associated with down-regulation of monocarboxylate transporters.
abstract: Mutations in isocitrate dehydrogenase 1 (IDH1) are characteristic of low-grade gliomas. We recently showed that mutant IDH1 cells reprogram cellular metabolism by down-regulating pyruvate dehydrogenase (PDH) activity. Reduced pyruvate metabolism via PDH could lead to increased pyruvate conversion to lactate. The goal of this study was therefore to investigate the impact of the IDH1 mutation on the pyruvate-to-lactate flux. We used 13C magnetic resonance spectroscopy and compared the conversion of hyperpolarized [1-13C]-pyruvate to [1-13C]-lactate in immortalized normal human astrocytes expressing mutant or wild-type IDH1 (NHAIDHmut and NHAIDHwt). Our results indicate that hyperpolarized lactate production is reduced in NHAIDHmut cells compared to NHAIDHwt. This reduction was associated with lower expression of the monocarboxylate transporters MCT1 and MCT4 in NHAIDHmut cells. Furthermore, hyperpolarized lactate production was comparable in lysates of NHAIDHmut and NHAIDHwt cells, wherein MCTs do not impact hyperpolarized pyruvate delivery and lactate production. Collectively, our findings indicated that lower MCT expression was a key contributor to lower hyperpolarized lactate production in NHAIDHmut cells. The SLC16A3 (MCT4) promoter but not SLC16A1 (MCT1) promoter was hypermethylated in NHAIDHmut cells, pointing to possibly different mechanisms mediating reduced MCT expression. Finally analysis of low-grade glioma patient biopsy data from The Cancer Genome Atlas revealed that MCT1 and MCT4 expression was significantly reduced in mutant IDH1 tumors compared to wild-type. Taken together, our study shows that reduced MCT expression is part of the metabolic reprogramming of mutant IDH1 gliomas. This finding could impact treatment and has important implications for metabolic imaging of mutant IDH1 gliomas.
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Pavithra
authors.initials: P
authors.lastname: Viswanath
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Chloe
authors.initials: C
authors.lastname: Najac
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Jose L
authors.initials: JL
authors.lastname: Izquierdo-Garcia
authors.affiliation: Department of Neurological Surgery, Helen Diller Research Center, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Aleksandr
authors.initials: A
authors.lastname: Pankov
authors.affiliation: Department of Neurological Surgery, Helen Diller Research Center, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Chibo
authors.initials: C
authors.lastname: Hong
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Pia
authors.initials: P
authors.lastname: Eriksson
authors.affiliation: Department of Neurological Surgery, Helen Diller Research Center, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Costello
authors.affiliation: Department of Neurological Surgery, Helen Diller Research Center, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Russell O
authors.initials: RO
authors.lastname: Pieper
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Sabrina M
authors.initials: SM
authors.lastname: Ronen
mesh_terms: D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D005910:Glioma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D027501:Monocarboxylic Acid Transporters / Q000096:biosynthesis*; D009124:Muscle Proteins / Q000096:biosynthesis*; D009154:Mutation; D027981:Symporters / Q000096:biosynthesis*; D000099233:Monocarboxylate Transport Protein 1
chemical_list: D007521:Isocitrate Dehydrogenase; D027501:Monocarboxylic Acid Transporters; D009124:Muscle Proteins; D027981:Symporters; D000099233:Monocarboxylate Transport Protein 1; C406962:SLC16A4 protein, human; C543588:IDH1 protein, human
keywords: MCT1; MCT4; magnetic resonance spectroscopy; metabolic reprogramming; mutant IDH1