Hydroxycarboxylic acid receptors are essential for breast cancer cells to control their lipid/fatty acid metabolism

// Claudia Stäubert 1,2,3 , Oliver Jay Broom 2 and Anders Nordström 1,2 1 Swedish Metabolomics Centre, Department of Forest Genetics and Plant Physiology, Swedish University of Agricultural Sciences, Umeå, Sweden 2 Department of Molecular Biology, Umeå University, Umeå, Sweden 3 Institute of Biochemistry, Faculty of Medicine, University of Leipzig, Leipzig, Germany Correspondence to: Claudia Stäubert, email: // Anders Nordström, email: // Keywords : hydroxycarboxylic acid receptors, cancer metabolism, metabolite-sensing GPCRs, GPR81, GPR109a Received : August 28, 2014 Accepted : February 26, 2015 Published : March 14, 2015 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 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 HCA 3 induced considerable breast cancer cell death as did knock-down of HCA 1 , although to a lesser extent. Liquid Chromatography Mass Spectrometry based analyses of breast cancer cell medium revealed a role for HCA 3 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 HCA 3 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.