title: Global profiling of metabolic adaptation to hypoxic stress in human glioblastoma cells.
abstract: Oncogenetic events and unique phenomena of the tumor microenvironment together induce adaptive metabolic responses that may offer new diagnostic tools and therapeutic targets of cancer. Hypoxia, or low oxygen tension, represents a well-established and universal feature of the tumor microenvironment and has been linked to increased tumor aggressiveness as well as resistance to conventional oncological treatments. Previous studies have provided important insights into hypoxia induced changes of the transcriptome and proteome; however, how this translates into changes at the metabolite level remains to be defined. Here, we have investigated dynamic, time-dependent effects of hypoxia on the cancer cell metabolome across all families of macromolecules, i.e., carbohydrate, protein, lipid and nucleic acid, in human glioblastoma cells. Using GC/MS and LC/MS/MS, 345 and 126 metabolites were identified and quantified in cells and corresponding media, respectively, at short (6 h), intermediate (24 h), and prolonged (48 h) incubation at normoxic or hypoxic (1% O2) conditions. In conjunction, we performed gene array studies with hypoxic and normoxic cells following short and prolonged incubation. We found that levels of several key metabolites varied with the duration of hypoxic stress. In some cases, metabolic changes corresponded with hypoxic regulation of key pathways at the transcriptional level. Our results provide new insights into the metabolic response of glioblastoma cells to hypoxia, which should stimulate further work aimed at targeting cancer cell adaptive mechanisms to microenvironmental stress.
authors: Department of Clinical Sciences, Section of Oncology and Pathology, Lund University, Lund, Sweden.
authors: Paulina
authors: P
authors: Kucharzewska
authors: Department of Clinical Sciences, Section of Oncology and Pathology, Lund University, Lund, Sweden.
authors: Helena C
authors: HC
authors: Christianson
authors: Department of Clinical Sciences, Section of Oncology and Pathology, Lund University, Lund, Sweden; Skåne Oncology Clinic, Skåne University Hospital, Lund, Sweden.
authors: Mattias
authors: M
authors: Belting
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology*; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D015687:Cell Hypoxia / Q000502:physiology*; D045744:Cell Line, Tumor; D002853:Chromatography, Liquid; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D020543:Proteome / Q000378:metabolism*; D053719:Tandem Mass Spectrometry; D059467:Transcriptome; D059016:Tumor Microenvironment / Q000502:physiology
chemical_list: D020543:Proteome
references: Curr Cancer Drug Targets. 2011 Jun;11(5):560-71
references: 21486217
references: Cell Stress Chaperones. 2010 Jul;15(4):387-94
references: 19902381
references: Nature. 2012 Nov 15;491(7424):364-73
references: 23151579
references: Cancer Cell. 2005 Oct;8(4):311-21
references: 16226706
references: Nat Rev Cancer. 2004 Jun;4(6):437-47
references: 15170446
references: Proc Natl Acad Sci U S A. 2013 Apr 30;110(18):7312-7
references: 23589885
references: Cell Metab. 2006 Mar;3(3):177-85
references: 16517405
references: Proc Natl Acad Sci U S A. 2011 Feb 22;108(8):3270-5
references: 21289278
references: Proc Natl Acad Sci U S A. 2014 Aug 5;111(31):E3234-42
references: 24938788
references: NMR Biomed. 2011 Jul;24(6):592-611
references: 21538631
references: J Biol Chem. 2007 Sep 14;282(37):27436-46
references: 17635920
references: Nat Rev Cancer. 2005 Jul;5(7):526-42
references: 16069816
references: Cell Metab. 2012 Oct 3;16(4):420-34
references: 22982021
references: Science. 2008 Feb 29;319(5867):1244-7
references: 18309083
references: Atherosclerosis. 2013 Jul;229(1):110-7
references: 23706521
references: Mol Cell. 2014 Jun 5;54(5):820-31
references: 24857547
references: Cell Metab. 2006 Mar;3(3):187-97
references: 16517406
references: Exp Diabetes Res. 2007;2007:61038
references: 18224243
references: Cancer Res. 2010 Aug 1;70(15):6368-76
references: 20647326
references: Proc Natl Acad Sci U S A. 2011 Dec 6;108(49):19611-6
references: 22106302
references: Am J Physiol. 1991 May;260(5 Pt 2):F650-6
references: 2035652
references: Mol Cell. 2010 Jun 25;38(6):864-78
references: 20620956
references: Proc Natl Acad Sci U S A. 2013 May 28;110(22):8882-7
references: 23671091
references: Semin Cancer Biol. 2009 Feb;19(1):12-6
references: 19114105
references: Cell Metab. 2012 Dec 5;16(6):751-64
references: 23177934
references: Cancer Res. 2012 Nov 15;72(22):5878-88
references: 23026133
references: FEBS J. 2012 Aug;279(15):2610-23
references: 22621751
references: Cell Rep. 2013 Apr 25;3(4):1175-86
references: 23583181
references: Int J Cancer. 2014 Jun 1;134(11):2748-53
references: 24243648
references: Toxicol Pathol. 2009 Jun;37(4):521-35
references: 19458390
references: Nature. 2011 Dec 22;480(7378):557-60
references: 22121020
references: Nat Rev Cancer. 2002 Jan;2(1):38-47
references: 11902584
references: Br J Cancer. 2002 Apr 8;86(7):1180-7
references: 11953869
references: Proc Natl Acad Sci U S A. 2004 May 25;101(21):8132-7
references: 15141079
references: PLoS One. 2011;6(9):e24411
references: 21912692
references: Cancer Cell. 2011 Mar 8;19(3):416-28
references: 21397863
references: Nat Rev Cancer. 2012 Nov;12(11):741-52
references: 23018234
references: Front Oncol. 2012 Feb 28;2:18
references: 22649778
references: Cell Metab. 2005 Mar;1(3):179-89
references: 16054061
references: N Engl J Med. 2005 Mar 10;352(10):987-96
references: 15758009
references: Kidney Int Suppl. 2000 Sep;77:S3-12
references: 10997684
references: Science. 2009 May 22;324(5930):1076-80
references: 19461003
references: Neuropathology. 2010 Jun;30(3):224-31
references: 19925564
references: Neuro Oncol. 2013 Sep;15(9):1186-99
references: 23658321
references: J Neurochem. 1998 Aug;71(2):775-83
references: 9681469
references: Anal Chem. 2009 Aug 15;81(16):6656-67
references: 19624122
references: Neuro Oncol. 2013 Sep;15(9):1114-26
references: 23877318
references: Cell. 2010 Jan 22;140(2):280-93
references: 20141841
references: Int J Cancer. 2006 Aug 1;119(3):484-92
references: 16496379
references: Cancer Chemother Pharmacol. 2013 Jan;71(1):13-20
references: 23073611
references: Oncogene. 2011 Jun 30;30(26):2986-96
references: 21358671
references: Mol Cell Proteomics. 2014 May;13(5):1198-218
references: 24567419
references: Biochem J. 2000 Aug 15;350 Pt 1:219-27
references: 10926847
references: Onco Targets Ther. 2013 Oct 08;6:1399-416
references: 24133372
references: Cell Cycle. 2011 Jun 1;10(11):1712-3
references: 21519190
references: Nat Rev Cancer. 2011 Dec;11(12):835-48
references: 22089420
references: Curr Opin Pharmacol. 2012 Dec;12(6):710-6
references: 22824431
references: Tumour Biol. 2014 Mar;35(3):2607-17
references: 24318988
references: Cancer Res. 2008 Jan 1;68(1):172-80
references: 18172309
references: Nature. 2012 Jan 19;481(7381):380-4
references: 22101433
references: Chem Biol Interact. 2003 Feb 1;143-144:363-71
references: 12604223
references: FEBS Lett. 2010 May 3;584(9):1872-8
references: 19913543
references: Prog Lipid Res. 2013 Oct;52(4):562-70
references: 23981365
references: J Biol Chem. 2011 Jul 8;286(27):24089-100
references: 21576240
references: Cancer Res. 2008 Nov 15;68(22):9291-301
references: 19010902