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Hydroxycarboxylic acid receptors are essential for breast cancer cells to control their lipid/fatty acid metabolism
Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Institute of Biochemistry, Faculty of Medicine, University of Leipzig, Leipzig, Germany.
Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
2015 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 6, no 23, 19706-19720 p.Article in journal (Refereed) Published
Abstract [en]

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 HCA(1) and HCA(3) 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 beta-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.

Place, publisher, year, edition, pages
2015. Vol. 6, no 23, 19706-19720 p.
Keyword [en]
hydroxycarboxylic acid receptors, cancer metabolism, metabolite-sensing GPCRs, GPR81, GPR109a
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:umu:diva-109457DOI: 10.18632/oncotarget.3565ISI: 000360135300040PubMedID: 25839160OAI: oai:DiVA.org:umu-109457DiVA: diva2:859686
Available from: 2015-10-08 Created: 2015-09-28 Last updated: 2017-12-01Bibliographically approved

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Stäubert, ClaudiaBroom, Oliver JayNordström, Anders
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