title: MYC-driven inhibition of the glutamate-cysteine ligase promotes glutathione depletion in liver cancer.
abstract: How MYC reprograms metabolism in primary tumors remains poorly understood. Using integrated gene expression and metabolite profiling, we identify six pathways that are coordinately deregulated in primary MYC-driven liver tumors: glutathione metabolism; glycine, serine, and threonine metabolism; aminoacyl-tRNA biosynthesis; cysteine and methionine metabolism; ABC transporters; and mineral absorption. We then focus our attention on glutathione (GSH) and glutathione disulfide (GSSG), as they are markedly decreased in MYC-driven tumors. We find that fewer glutamine-derived carbons are incorporated into GSH in tumor tissue relative to non-tumor tissue. Expression of GCLC, the rate-limiting enzyme of GSH synthesis, is attenuated by the MYC-induced microRNA miR-18a. Inhibition of miR-18ain vivoleads to increased GCLC protein expression and GSH abundance in tumor tissue. Finally, MYC-driven liver tumors exhibit increased sensitivity to acute oxidative stress. In summary, MYC-dependent attenuation of GCLC by miR-18a contributes to GSH depletionin vivo, and low GSH corresponds with increased sensitivity to oxidative stress in tumors. Our results identify new metabolic pathways deregulated in primary MYC tumors and implicate a role for MYC in regulating a major antioxidant pathway downstream of glutamine.
authors.affiliation: Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA, USA.|Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: Brittany
authors.initials: B
authors.lastname: Anderton
authors.affiliation: Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA, USA.|Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: Roman
authors.initials: R
authors.lastname: Camarda
authors.affiliation: Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA, USA.|Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Balakrishnan
authors.affiliation: Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA, USA.|Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.|Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, TWINCORE, Center for Experimental and Clinical Infection Research, Hannover, Germany.
authors.forename: Asha
authors.initials: A
authors.lastname: Balakrishnan
authors.affiliation: Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA, USA.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Kohnz
authors.affiliation: Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA, USA.|Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: Lionel
authors.initials: L
authors.lastname: Lim
authors.affiliation: Department of Pathology and Huntsman Cancer Institute, University of Utah, Salt Lake, UT, USA.
authors.forename: Kimberley J
authors.initials: KJ
authors.lastname: Evason
authors.affiliation: Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA, USA.|Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Momcilovic
authors.affiliation: Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA, USA.|Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: Klaus
authors.initials: K
authors.lastname: Kruttwig
authors.affiliation: Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Huang
authors.affiliation: Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
authors.forename: Guowang
authors.initials: G
authors.lastname: Xu
authors.affiliation: Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA, USA.
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Nomura
authors.affiliation: Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA, USA Andrei.goga@ucsf.edu.|Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: Andrei
authors.identifier: 0000-0001-9127-0986
authors.initials: A
authors.lastname: Goga
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005721:Glutamate-Cysteine Ligase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism*; D053858:Metabolic Networks and Pathways / Q000235:genetics; D055442:Metabolome; D055432:Metabolomics / Q000379:methods; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics; D018384:Oxidative Stress; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference
chemical_list: C581632:MIRN18 microRNA, human; D035683:MicroRNAs; D016271:Proto-Oncogene Proteins c-myc; D005973:Glutamine; C000609392:GCLC protein, human; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione
keywords: 
  MYC
  ; cancer; glutathione; metabolism; miRNA