title: CCL5 activation of CCR5 regulates cell metabolism to enhance proliferation of breast cancer cells.
abstract: In earlier studies, we showed that CCL5 enhances proliferation and survival of MCF-7 breast cancer cells in an mTOR-dependent manner and we provided evidence that, for T cells, CCL5 activation of CCR5 results in increased glycolysis and enhanced ATP production. Increases in metabolic activity of cancer cells, specifically increased glycolytic activity and increased expression of glucose transporters, are associated with tumour progression. In this report, we provide evidence that CCL5 enhances the proliferation of human breast cancer cell lines (MDA-MB-231, MCF-7) and mouse mammary tumour cells (MMTV-PyMT), mediated by CCR5 activation. Concomitant with enhanced proliferation we show that CCL5 increases cell surface expression of the glucose transporter GLUT1, and increases glucose uptake and ATP production by these cells. Blocking CCL5-inducible glucose uptake abrogates the enhanced proliferation induced by CCL5. We provide evidence that increased glucose uptake is associated with enhanced glycolysis, as measured by extracellular acidification. Moreover, CCL5 enhances the invasive capacity of these breast cancer cells. Using metabolomics, we demonstrate that the metabolic signature of CCL5-treated primary mouse mammary tumour cells reflects increased anabolic metabolism. The implications are that CCL5-CCR5 interactions in the tumour microenvironment regulate metabolic events, specifically glycolysis, to promote tumour proliferation and invasion.
authors.affiliation: Toronto General Research Institute, University Health Network, Toronto, Canada Department of Immunology, University of Toronto, Toronto, Canada.
authors.forename: Darrin
authors.initials: D
authors.lastname: Gao
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
authors.forename: Ramtin
authors.initials: R
authors.lastname: Rahbar
authors.affiliation: Toronto General Research Institute, University Health Network, Toronto, Canada Department of Immunology, University of Toronto, Toronto, Canada en.fish@utoronto.ca.
authors.forename: Eleanor N
authors.initials: EN
authors.lastname: Fish
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D018946:Chemokine CCL5 / Q000378:metabolism*; D005260:Female; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D061986:MCF-7 Cells; D055432:Metabolomics / Q000379:methods*; D051379:Mice; D019713:Receptors, CCR5 / Q000378:metabolism*
chemical_list: C483024:CCL5 protein, human; C584933:CCR5 protein, human; D018946:Chemokine CCL5; D051272:Glucose Transporter Type 1; D019713:Receptors, CCR5; C495677:SLC2A1 protein, human
keywords: CCL5; CCR5; anabolic metabolism; breast cancer; glycolysis