ABSTRACT
Activator and inhibitor roles for the 88-kDa-secreted glycoprotein progranulin (PGRN) have been demonstrated in ovarian cancer cells. Here, we investigated the effects of PGRN in breast cancer migration. Testing MCF7, MDA-MB-453, and MDA-MB-231 human breast cancer cells and the MCF10A breast epithelial cell line, we demonstrate that LPA-induced PGRN stimulation led to a significant increase in cell invasion of MDA-MB-453 and MDA-MB-231 cells only (p<0.05). Moreover, incubation with an anti-PGRN antibody, an inhibitor of the ERK pathway (PD98059) or both in combination inhibited the ability of MDA-MB-231 cells to invade. Furthermore, the expression of focal adhesion kinases promoted by LPA-induced PGRN was also inhibited by PD98059 alone or in combination with an anti-PGRN antibody (p<0.05). Taken together, these results suggest that the LPA activation of PGRN involving the ERK pathway is critical to promote MDA-MB-231 breast cancer cell invasion.
Subject(s)
Breast Neoplasms/pathology , Cell Movement , Gene Expression Regulation, Neoplastic , Intercellular Signaling Peptides and Proteins/metabolism , Lysophospholipids/pharmacology , Antibodies/metabolism , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Cell Line, Tumor , Female , Flavonoids/pharmacology , Focal Adhesion Kinase 1/genetics , Focal Adhesion Kinase 1/metabolism , Humans , Intercellular Signaling Peptides and Proteins/genetics , MAP Kinase Signaling System , Neoplasm Invasiveness/pathology , Progranulins , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , TransfectionABSTRACT
We investigated the effects of the endothelin-1 (ET-1) receptor dual antagonist (Bosentan®) on the inflammatory cytokines and the chemoattractant molecules associated with breast cancer growth and the development of tumor infiltration in bone explants. Immunocompetent mice implanted with the murine mammary carcinoma 4T1 cells in a skin-fold chamber and treated with Bosentan® had reduced tumor growth (p < .05). ET-1 promoted the secretion of the anti-inflammatory soluble tumor necrosis factor (TNF) receptor and IL12 p40 in vitro. The Bosentan® treatment in vivo was associated with a local increase of the anti-inflammatory IL-1α cytokine concentration and decrease of the pro-inflammatory TNF-α and IL-17 cytokine concentrations (p < .05).
Subject(s)
Cell Movement/drug effects , Cytokines/metabolism , Mammary Neoplasms, Experimental/prevention & control , Sulfonamides/pharmacology , Animals , Antihypertensive Agents/pharmacology , Bone Neoplasms/metabolism , Bone Neoplasms/prevention & control , Bone Neoplasms/secondary , Bosentan , Cell Line , Cell Line, Tumor , Cell Proliferation/drug effects , Endothelin Receptor Antagonists , Endothelin-1/pharmacology , Enzyme-Linked Immunosorbent Assay , Female , Inflammation Mediators/metabolism , Interleukin-17/metabolism , Interleukin-1alpha/metabolism , Male , Mammary Neoplasms, Experimental/metabolism , Mammary Neoplasms, Experimental/pathology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Neutrophils/drug effects , Neutrophils/pathology , Receptors, Endothelin/genetics , Reverse Transcriptase Polymerase Chain Reaction , Tumor Burden/drug effects , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Drug delivery systems offer the advantage of sustained targeted release with minimal side effect. In the present study, the therapeutic efficacy of a porous silica-calcium phosphate nanocomposite (SCPC) as a new delivery system for 5-Fluorouracil (5-FU) was evaluated in vitro and in vivo. In vitro studies showed that two formulations; SCPC50/5-FU and SCPC75/5-FU hybrids were very cytotoxic for 4T1 mammary tumor cells. In contrast, control SCPCs without drug did not show any measurable toxic effect. Release kinetics studies showed that SCPC75/5-FU hybrid provided a burst release of 5-FU in the first 24 h followed by a sustained release of a therapeutic dose (30.7 microg/day) of the drug for up to 32 days. Moreover, subcutaneous implantation of SCPC75/5-FU hybrid disk in an immunocompetent murine model of breast cancer stopped 4T1 tumor growth. Blood analyses showed comparable concentrations of Ca, P and Si in animals implanted with or without SCPC75 disks. These results strongly suggest that SCPC/5-FU hybrids can provide an effective treatment for solid tumors with minimal side effects.
