Abstract
BackgroundWe previously discovered that tetracyclines increase the expression of lipid phosphate phosphatases at the surface of cells. These enzymes degrade circulating lysophosphatidate and therefore doxycycline increases the turnover of plasma lysophosphatidate and decreases its concentration. Extracellular lysophosphatidate signals through six G protein-coupled receptors and it is a potent promoter of tumor growth, metastasis and chemo-resistance. These effects depend partly on the stimulation of inflammation that lysophosphatidate produces.MethodsIn this work, we used a syngeneic orthotopic mouse model of breast cancer to determine the impact of doxycycline on circulating lysophosphatidate concentrations and tumor growth. Cytokine/chemokine concentrations in tumor tissue and plasma were measured by multiplexing laser bead technology. Leukocyte infiltration in tumors was analyzed by immunohistochemistry. The expression of IL-6 in breast cancer cell lines was determined by RT-PCR. Cell growth was measured in Matrigel™ 3D culture. The effects of doxycycline on NF-κB-dependent signaling were analyzed by Western blotting.ResultsDoxycycline decreased plasma lysophosphatidate concentrations, delayed tumor growth and decreased the concentrations of several cytokines/chemokines (IL-1β, IL-6, IL-9, CCL2, CCL11, CXCL1, CXCL2, CXCL9, G-CSF, LIF, VEGF) in the tumor. These results were compatible with the effects of doxycycline in decreasing the numbers of F4/80+ macrophages and CD31+ blood vessel endothelial cells in the tumor. Doxycycline also decreased the lysophosphatidate-induced growth of breast cancer cells in three-dimensional culture. Lysophosphatidate-induced Ki-67 expression was inhibited by doxycycline. NF-κB activity in HEK293 cells transiently expressing a NF-κB-luciferase reporter vectors was also inhibited by doxycycline. Treatment of breast cancer cells with doxycycline also decreased the translocation of NF-κB to the nucleus and the mRNA levels for IL-6 in the presence or absence of lysophosphatidate.ConclusionThese results contribute a new dimension for understanding the anti-inflammatory effects of tetracyclines, which make them potential candidates for adjuvant therapy of cancers and other inflammatory diseases.
Highlights
We previously discovered that tetracyclines increase the expression of lipid phosphate phosphatases at the surface of cells
We recently discovered that tetracyclines increase extracellular LPA degradation by enhancing the stabilities of LPP1, LPP2 and LPP3 in several breast cancer cell lines and in non-transformed cells [31]
Doxycycline delayed tumor growth and decreased the numbers of tumor-associated macrophages and blood vessels in a syngeneic orthotopic mouse model of breast cancer We recently discovered that doxycycline increased the dephosphorylation of extracellular LPA in MDA-MB231, MCF-7 and 4T1 breast cancer cells by increasing the expression of the Lipid phosphate phosphatase (LPP) on the cell surface [31]
Summary
We previously discovered that tetracyclines increase the expression of lipid phosphate phosphatases at the surface of cells. Extracellular lysophosphatidate signals through six G protein-coupled receptors and it is a potent promoter of tumor growth, metastasis and chemo-resistance These effects depend partly on the stimulation of inflammation that lysophosphatidate produces. Increased LPA signaling is closely associated with tumor growth and cancer-related inflammation [10,11,12,13] This is because LPA induces the expression of inflammatory cytokines through activating nuclear factor-κB (NF-κB) [14, 15]. The high LPA concentration enhances lymphocyte infiltration, which increases the inflammatory status in the tumor This vicious cycle of LPA signaling increases the production of inflammatory mediators, which further increases tumor growth, metastasis and the development of chemo-resistance [10, 11, 16]. TAMs promote angiogenesis by producing vascular endothelial growth factor (VEGF) [24] and suppress antitumor immunity by secreting immune regulatory molecules such as IL-10 [25] and transform growth factor β (TGFβ) [26]
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