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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.

SUBMITTER: Gao D

PROVIDER: S-EPMC4929946 | biostudies-literature |

REPOSITORIES: biostudies-literature

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CCL5 mediates breast cancer metastasis and prognosis through CCR5/Treg cells.

Project description:Background and aimsCCL5 is considered to contribute to the biological function of a variety of cancer types, but its specific mechanism is still unclear. This study aimed to reveal the mechanism of CCL5 in the invasion, metastasis, and prognosis of breast cancer.MethodsThe expression of CCL5 in tumor tissue and serum was measured with a Luminex protein detection kit, and the correlation between CCL5 and clinical parameters was evaluated. Kaplan-Meier analysis was used to analyze the effect of CCL5 on the prognosis of breast cancer patients. Protein interaction network analysis and gene coexpression were used to determine the receptor that has the strongest interaction with CCL5. Enrichment analysis was used to study the possible pathway by which CCL5 affects breast cancer progression. We used immunofluorescence staining and flow cytometry to estimate the fraction of immunity-related components in the tumor microenvironment.ResultsThe expression level of CCL5 in breast cancer patients was positively correlated with the degree of axillary lymph node metastasis; CCL5 in tumor tissue was correlated with estrogen receptor status (P = 0.034), progesterone receptor (P = 0.009), nuclear grade (P = 0.013), clinical stage (P < 0.001) and molecular subtype (P = 0.024) in breast cancer patients. Breast cancer patients with high CCL5 expression had worse disease-free survival (P = 0.031) and breast cancer-specific survival (P = 0.043); however, CCL5 had no effect on overall survival (P = 0.077). CCL5 affected tumor progression through CCR5, and the T-cell-related immune pathway may be the main pathway; the CD4+/CD8+, CCR5+/CD4+ and Treg/CCR5+ cell ratios were significantly increased in the lymph node metastasis group.ConclusionCCL5 affects the Treg/CD4+CCR5+ cell ratio in breast cancer patients through CCR5, thus affecting breast cancer metastasis and prognosis.

| S-EPMC9399502 | biostudies-literature

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CCR5/CCL5 axis interaction promotes migratory and invasiveness of pancreatic cancer cells.

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Targeting Autocrine CCL5-CCR5 Axis Reprograms Immunosuppressive Myeloid Cells and Reinvigorates Antitumor Immunity.

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| S-EPMC6884928 | biostudies-literature

CCL5/CCR5 axis in human diseases and related treatments.

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| S-EPMC8423937 | biostudies-literature

Macrophage Cytokines Enhance Cell Proliferation of Normal Prostate Epithelial Cells through Activation of ERK and Akt.

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| S-EPMC5955920 | biostudies-literature

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