title: Hydroxycarboxylic acid receptors are essential for breast cancer cells to control their lipid/fatty acid metabolism.
abstract: Cancer cells exhibit characteristic changes in their metabolism with efforts being made to address them therapeutically. However, targeting metabolic enzymes as such is a major challenge due to their essentiality for normal proliferating cells. The most successful pharmaceutical targets are G protein-coupled receptors (GPCRs), with more than 40% of all currently available drugs acting through them.We show that, a family of metabolite-sensing GPCRs, the Hydroxycarboxylic acid receptor family (HCAs), is crucial for breast cancer cells to control their metabolism and proliferation.We found HCA1 and HCA3 mRNA expression were significantly increased in breast cancer patient samples and detectable in primary human breast cancer patient cells. Furthermore, siRNA mediated knock-down of HCA3 induced considerable breast cancer cell death as did knock-down of HCA1, although to a lesser extent. Liquid Chromatography Mass Spectrometry based analyses of breast cancer cell medium revealed a role for HCA3 in controlling intracellular lipid/fatty acid metabolism. The presence of etomoxir or perhexiline, both inhibitors of fatty acid β-oxidation rescues breast cancer cells with knocked-down HCA3 from cell death.Our data encourages the development of drugs acting on cancer-specific metabolite-sensing GPCRs as novel anti-proliferative agents for cancer therapy.
authors.affiliation: Swedish Metabolomics Centre, Department of Forest Genetics and Plant Physiology, Swedish University of Agricultural Sciences, Umeå, Sweden.|Department of Molecular Biology, Umeå University, Umeå, Sweden.|Institute of Biochemistry, Faculty of Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Stäubert
authors.affiliation: Department of Molecular Biology, Umeå University, Umeå, Sweden.
authors.forename: Oliver Jay
authors.initials: OJ
authors.lastname: Broom
authors.affiliation: Swedish Metabolomics Centre, Department of Forest Genetics and Plant Physiology, Swedish University of Agricultural Sciences, Umeå, Sweden.|Department of Molecular Biology, Umeå University, Umeå, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Nordström
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D016923:Cell Death; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002853:Chromatography, Liquid; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004852:Epoxy Compounds / Q000494:pharmacology; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects; D010084:Oxidation-Reduction; D010480:Perhexiline / Q000494:pharmacology; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D053719:Tandem Mass Spectrometry; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; D005227:Fatty Acids; C533610:HCAR1 protein, human; C473653:HCAR3 protein, human; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D011978:Receptors, Nicotinic; D002334:Carnitine O-Palmitoyltransferase; D010480:Perhexiline; C054207:etomoxir
keywords: GPR109a; GPR81; cancer metabolism; hydroxycarboxylic acid receptors; metabolite-sensing GPCRs
references.citation: Science. 2000 Mar 17;287(5460):1960-4
references.pmid: 10720314
references.citation: J Inherit Metab Dis. 2000 Nov;23(7):745-50
references.pmid: 11117435
references.citation: Clin Chem. 2002 Jan;48(1):176-9
references.pmid: 11751554
references.citation: Genome Biol. 2002 Jun 18;3(7):RESEARCH0034
references.pmid: 12184808
references.citation: Cancer Res. 2004 Aug 1;64(15):5245-50
references.pmid: 15289330
references.citation: Cancer Res. 1988 Dec 15;48(24 Pt 1):7264-72
references.pmid: 3191497
references.citation: Clin Chem. 1998 Mar;44(3):463-71
references.pmid: 9510849
references.citation: J Biol Chem. 2005 Jul 22;280(29):26649-52
references.pmid: 15929991
references.citation: J Med Chem. 2006 Feb 23;49(4):1227-30
references.pmid: 16480258
references.citation: Biochem Biophys Res Commun. 2008 Dec 19;377(3):987-91
references.pmid: 18952058
references.citation: J Biol Chem. 2009 Jan 30;284(5):2811-22
references.pmid: 19047060
references.citation: Clin Chem. 2009 Apr;55(4):611-22
references.pmid: 19246619
references.citation: Cancer Res. 2009 Apr 1;69(7):2826-32
references.pmid: 19276343
references.citation: Science. 2009 May 22;324(5930):1029-33
references.pmid: 19460998
references.citation: Methods Mol Biol. 2009;552:51-66
references.pmid: 19513641
references.citation: J Biol Chem. 2009 Aug 14;284(33):21928-33
references.pmid: 19561068
references.citation: Trends Pharmacol Sci. 2009 Nov;30(11):557-62
references.pmid: 19837462
references.citation: Biochim Biophys Acta. 2010 Mar;1801(3):381-91
references.pmid: 19782152
references.citation: Cell Metab. 2010 Apr 7;11(4):311-9
references.pmid: 20374963
references.citation: J Clin Invest. 2010 Aug;120(8):2910-9
references.pmid: 20664170
references.citation: Pharmacol Rev. 2011 Jun;63(2):269-90
references.pmid: 21454438
references.citation: Nat Rev Drug Discov. 2011 Sep;10(9):671-84
references.pmid: 21878982
references.citation: J Pharmacol Exp Ther. 2012 Jun;341(3):794-801
references.pmid: 22434674
references.citation: Br J Pharmacol. 2012 Jul;166(6):1756-73
references.pmid: 22289163
references.citation: Nat Rev Drug Discov. 2012 Aug;11(8):603-19
references.pmid: 22790105
references.citation: BMC Bioinformatics. 2012;13:134
references.pmid: 22708584
references.citation: Cell Cycle. 2012 Nov 1;11(21):3964-71
references.pmid: 23082722
references.citation: Cell Death Dis. 2013;4:e532
references.pmid: 23470539
references.citation: Nat Rev Cancer. 2013 Apr;13(4):227-32
references.pmid: 23446547
references.citation: Biochim Biophys Acta. 2013 Sep;1831(9):1467-74
references.pmid: 23850792
references.citation: Annu Rev Pharmacol Toxicol. 2014;54:407-34
references.pmid: 24160702
references.citation: Immunity. 2014 Jan 16;40(1):128-39
references.pmid: 24412617
references.citation: Cancer Res. 2014 Feb 15;74(4):1166-78
references.pmid: 24371223
references.citation: Cell Signal. 2014 Jul;26(7):1466-75
references.pmid: 24662263
references.citation: Cancer Res. 2014 Sep 15;74(18):5301-10
references.pmid: 24928781