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.
Highlights
Inflammation is critical in tumour progression [1,2,3], creating a tumour microenvironment largely defined by soluble secreted factors and an influx of inflammatory cells
We provided evidence that CCL5 treatment promotes the proliferation of MCF-7 human breast cancer cells, through mTOR-dependent mRNA translation of a subset of proteins associated with cell cycle progression and survival [13]. mRNA translation is an energy dependent process
In a first series of experiments, we examined the effects of CCL5 on activation of the AKT/ mTOR pathway in MDA-MB-231 human breast cancer cells
Summary
Inflammation is critical in tumour progression [1,2,3], creating a tumour microenvironment largely defined by soluble secreted factors and an influx of inflammatory cells. Together, these participate in the neoplastic process to regulate the proliferation, survival and migration of tumour cells [4,5]. Chemokine binding to G protein-coupled receptors initiates signalling cascades that promote directional migration through cytoskeletal rearrangement, cell polarization and integrin activation. Chemokines regulate numerous migration-unrelated responses, including cell survival, apoptosis, protein translation, embryogenesis, angiogenesis and tumour growth [6]. In the context of breast cancer, chemokines have been implicated in promoting the malignant phenotype: CXCL3, CXCL12, CXCL13, CCL21 and CCL5 are associated with tumour progression and metastasis in breast cancer [7,8,9,10,11]
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