ABSTRACT
Histone deacetylase inhibitors (HDACi) have been described as multifunctional anticancer agents. The failure of conventional therapy for glioblastoma (GBM) renders this tumor an attractive target for immunotherapy. Innate immune cells, such as natural killer (NK) cells, play a crucial role in antitumor immune responses. Here, we describe how the HDACi trichostatin A (TSA) promotes apoptosis of tumor cells, as well as augments anti-GBM innate immune responses. In vitro treatment of GBM cells with TSA results in an up-regulation of the natural killer group-2 member-D (NKG2D) ligands major histocompatibility complex class I-related chain (MIC)-A and UL16 binding protein (ULBP)-2 at both mRNA and protein levels, rendering them susceptible to NK cell-mediated lysis. In vivo, TSA delays tumor growth of GBM xenografts. Both the in vitro and in vivo antitumor effect of TSA was significantly reduced by blocking NK cell activity. Our data suggest that HDACi, especially in combination with other clinical immunotherapeutical approaches, may be considered in a combined therapeutic approach for GBM.
Subject(s)
Apoptosis/drug effects , Brain Neoplasms/pathology , Cell Proliferation/drug effects , Glioblastoma/pathology , Histone Deacetylase Inhibitors/pharmacology , Hydroxamic Acids/pharmacology , Killer Cells, Natural/immunology , Animals , Blotting, Western , Brain Neoplasms/drug therapy , Brain Neoplasms/immunology , Cytotoxicity, Immunologic , Female , Flow Cytometry , GPI-Linked Proteins/genetics , GPI-Linked Proteins/metabolism , Glioblastoma/drug therapy , Glioblastoma/immunology , Histocompatibility Antigens Class I/genetics , Histocompatibility Antigens Class I/metabolism , Humans , Intercellular Signaling Peptides and Proteins/genetics , Intercellular Signaling Peptides and Proteins/metabolism , Killer Cells, Natural/metabolism , Killer Cells, Natural/pathology , Mice , Mice, Nude , NK Cell Lectin-Like Receptor Subfamily K/genetics , NK Cell Lectin-Like Receptor Subfamily K/metabolism , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Receptors, TNF-Related Apoptosis-Inducing Ligand/genetics , Receptors, TNF-Related Apoptosis-Inducing Ligand/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction/drug effects , TNF-Related Apoptosis-Inducing Ligand/genetics , TNF-Related Apoptosis-Inducing Ligand/metabolism , Tumor Cells, CulturedABSTRACT
Mithramycin A (MitA) is a chemotherapeutic compound which has been used in the therapy of several types of cancer. For experimental cancer it has been shown that MitA mediates the expression of genes involved in tumor progression such as genes involved in immunosurveillance, cell motility or cell death. MitA works synergistically with Apo2L/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), and with antiangiogenic agents. We were therefore interested in analyzing whether MitA might be a suitable agent for glioma therapy. We demonstrate herein that the cell death sensitizing effects of MitA are cell line specific, independent of the endogenous status of the tumor suppressor p53 as well as of the endogenous expression of X-linked inhibitor of apoptosis (XIAP) or basal sensitivity towards death ligand-induced cell death. In glioma cells, MitA reduced the secretion and activity of the migration-involved matrix metalloproteinases (MMP), diminished vascular endothelial growth factor (VEGF), and increased recepteur d'origine nantais (RON) kinase messenger RNA (mRNA), paralleled by a significant reduction of glioma cell migration. In contrast to other cancer types, in glioma cells MitA did not alter the expression of the immunorelevant genes major histocompatibility complex I class related (MIC)-A, MIC-B or UL16 binding proteins (ULBP). We conclude that, whereas MitA-mediated reduction of XIAP expression and sensitization to Apo2L/TRAIL are cell line specific, its antimigratory effects are more general and might be the result of altered expression of MMP, VEGF, and/or RON kinase. Therefore, MitA might be a potential agent to reduce glioma cell migration.
