Hydroxycarboxylic acid receptors are essential for breast cancer cells to control their lipid/fatty acid metabolism
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Claudia Stäubert1,2,3, Oliver Jay Broom2 and Anders Nordström1,2
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
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
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.
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