89 : A role for CCL5 in breast cancer cell metabolism

Abstract

The inflammatory chemokine, CCL5, activates its cognate receptor, CCR5, to initiate a number of responses including chemotaxis, cell growth and apoptosis. We have shown that CCL5-mediated mTOR activation influences T cell chemotaxis by initiating the translation of proteins implicated in cell migration, including MMP-9 and cyclin D1. Rapid production of these proteins may prime T cells for efficient migration. Recently, we provided evidence that, for T cells, CCL5 activation of CCR5 results in increased glycolysis, enhanced ATP production and activation of the nutrient sensing AMPK pathway, all associated with enabling CCL5-mediated chemotaxis. Viewed altogether, our data suggest that in addition to influencing cell growth/apoptosis and providing migrational cues for T cells, CCL5-CCR5 interactions increase energy supplies to match the energy demands of chemotaxis. Several studies have demonstrated a pivotal role for CCL5–CCR5 interactions in breast cancer progression: CCL5 is highly expressed in high grade tumors and is a predictor of rapid disease progression in stage II and III breast cancer patients. Conversely, patients with benign breast disorders express low levels of CCL5. Breast cancer cell lines respond to and migrate towards CCL5, and secrete physiological levels of CCL5 in culture. We have shown that at physiological levels, CCL5 enhances proliferation of the breast cancer cell line, MCF-7.CCR5. CCL5 induces the formation of the eIF4F translation initiation complex through an mTOR-dependent process and initiates mRNA translation for proteins associated with cell proliferation, thereby providing CCR5-positive breast cancer cells with a proliferative advantage. Cancer cells are more dependent on glycolysis than non-dividing cells for ATP generation and metabolite flux. Glycolysis is associated with nucleotide synthesis and lactate acidification of the microenvironment, promoting angiogenesis and tumor invasion of the basement membrane. Accordingly, we conducted studies to investigate whether CCL5 activation of CCR5 will influence metabolic events that would enhance tumor growth, tissue invasion and metastases. We provide evidence that in both primary mouse breast cancer tumors and in a panel of breast cancer cell lines, CCL5–CCR5 interactions lead to increased proliferation associated with CCL5–CCR5 mediated increased glucose uptake, increased ATP production, and enhanced glycolysis, associated with extracellular acidification. These data suggest that targeting CCL5–CCR5 interactions that invoke tumor metabolism may be an effective therapeutic strategy to limit tumor growth.