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1.
J Cardiovasc Pharmacol ; 36(5 Suppl 1): S354-6, 2000 Nov.
Article in English | MEDLINE | ID: mdl-11078419

ABSTRACT

An imbalance between proliferation and apoptosis is important in tumor progression. Endothelin-1 (ET-1) has vasoconstricting and mitogenic activities and may be involved in apoptosis regulation. We found that ET-1 and FasL systems were colocalized in human colon tumors and that ET-1 was secreted by human (HT-29, SW480) and rat (PROb, REGb) colon carcinoma cell lines. Bosentan, a mixed endothelin-A- and -B- (ET(A)/ET(B)) receptor antagonist, potentiated FasL- (APO-1, CD95) induced apoptosis in these cells. The specific inhibition of enzymes involved in ceramide production did not restore survival of cells exposed to FasL and bosentan. Inhibition of PKC with bisindolylmaleimide IX enhanced FasL-induced apoptosis in HT-29, PROb and REGb cells in the absence of bosentan. These results suggest that ET-1 is an autocrine survival factor able to protect colon carcinoma cells against FasL-induced apoptosis, involving the protein kinase C (PKC) but not the sphingomyelin-ceramide signaling transduction pathways.


Subject(s)
Apoptosis/drug effects , Colonic Neoplasms/pathology , Endothelin Receptor Antagonists , Membrane Glycoproteins/physiology , Protein Kinase C/physiology , Sulfonamides/pharmacology , Animals , Bosentan , Fas Ligand Protein , Rats , Receptor, Endothelin A , Receptor, Endothelin B , Tumor Cells, Cultured
2.
Lab Invest ; 80(11): 1681-9, 2000 Nov.
Article in English | MEDLINE | ID: mdl-11092528

ABSTRACT

Endothelin-1 (ET-1) is a powerful mitogenic and/or anti-apoptotic peptide produced by many cancer cells. To evaluate the potential role of the endothelin system in glioblastoma we first determined the cellular distribution of the mRNA and proteins of the components of the endothelin system, preproendothelin-1 (PPET-1), endothelin-converting enzyme-1 (ECE-1), and ET(A) and ET(B) receptors in human glioblastoma tissue and glioblastoma cell lines. PPET-1, ECE-1, and ET(A) receptor were highly expressed in glioblastoma vessels and in some scattered glioblastoma areas whereas ET(B) receptor was mainly found in cancer cells. This suggests that glioblastoma vessels constitute an important source of ET-1 that acts on cancer cells via the ET(B) receptor. Four human glioblastoma cell lines expressed mRNA for all of the components of the ET-1 pathway. Bosentan, a mixed ET(A) and ET(B) receptor antagonist, induced apoptosis in these cell lines in a dose-dependent manner. Apoptosis was potentiated by Fas Ligand (APO-1L, CD95L), a pro-apoptotic peptide, only in LNZ308 cells, corresponding to the known functional Fas expression in these cell lines. LNZ308 cells also expressed the long and short forms of the cellular FLICE/caspase-8 inhibitory protein (FLIP). Bosentan and a protein kinase C inhibitor down-regulated short FLIP in these cells. ET-1 induced transient phosphorylation of extracellular signal-regulated kinase but did not induce long-term thymidine incorporation in LNZ308 glioblastoma cells. These results suggest that, in glioblastoma cells, ET-1, mainly acting via the ET(B) receptor, is a survival/antiapoptotic factor produced by tumor vasculature, but not a proliferation factor, involving protein kinase C and extracellular signal-regulated kinase pathways, and stabilization of the short form of FLIP.


Subject(s)
Brain Neoplasms/physiopathology , Endothelin-1/physiology , Glioblastoma/physiopathology , Base Sequence , DNA Primers , Endothelin-1/genetics , Fas Ligand Protein , Humans , Immunohistochemistry , Membrane Glycoproteins/physiology , RNA, Messenger/genetics , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Tumor Cells, Cultured , fas Receptor/physiology
3.
Int J Cancer ; 86(2): 182-7, 2000 Apr 15.
Article in English | MEDLINE | ID: mdl-10738244

ABSTRACT

Imbalanced proliferation and apoptosis is important in tumor progression. Endothelin (ET)-1, a 21-amino-acid peptide with vasoconstricting and mitogenic activities, has been shown to be involved in the regulation of apoptosis. Progressive and regressive rat colon (PROb and REGb cells) carcinoma cell lines express the components of the ET-1 system (preproET-1, ET-converting enzyme and ET-receptors) and secrete ET-1. These cells also express the Fas(APO-1, CD95)/FasL system, but are resistant to FasL-induced apoptosis. We thus addressed the role of ET-1 in FasL-dependent cell death. Bosentan, a mixed ET(A)/ET(B) receptor antagonist, potentiated FasL-induced apoptosis in these cells. At low concentrations (10(-13) to 10(-10) M), ET-1 dose-dependently reversed bosentan-induced apoptosis. Bosentan sensitization to FasL-induced apoptosis was not mediated by increased expression of Fas receptor and was blocked by the caspase inhibitor zVAD-fmk. The specific inhibition of enzymes involved in ceramide production did not restore survival of cells exposed to FasL and bosentan. Our results suggest that ET-1 is a survival factor able to protect in vitro colon carcinoma cells against FasL-induced apoptosis.


Subject(s)
Apoptosis , Colonic Neoplasms/pathology , Endothelin Receptor Antagonists , Membrane Glycoproteins/pharmacology , Adenocarcinoma/chemistry , Adenocarcinoma/metabolism , Adenocarcinoma/pathology , Animals , Aspartic Acid Endopeptidases/genetics , Bosentan , Caspase Inhibitors , Colonic Neoplasms/chemistry , Colonic Neoplasms/metabolism , Drug Synergism , Endothelin-1/metabolism , Endothelin-1/physiology , Endothelin-Converting Enzymes , Endothelins/genetics , Enzyme Inhibitors/pharmacology , Fas Ligand Protein , Humans , Membrane Glycoproteins/physiology , Metalloendopeptidases , Protein Precursors/genetics , RNA, Messenger/analysis , Rats , Receptors, Endothelin/genetics , Receptors, Endothelin/physiology , Sulfonamides/pharmacology , Tumor Cells, Cultured , fas Receptor/biosynthesis
4.
Eur J Immunol ; 26(11): 2709-16, 1996 Nov.
Article in English | MEDLINE | ID: mdl-8921959

ABSTRACT

Immunodominance (ID) of T cell epitopes is a well-documented phenomenon that might have profound significance in the evolution of T cell responses to pathogens, tumors, autoantigens and vaccines. With the intention of developing vaccines composed of several cytotoxic T cell (CTL) epitopes, we injected mice with peptide mixtures containing two to five CTL epitopes and observed clear patterns of ID. In a first case, ID strictly correlated with the competitor activity of the individual peptides for H-2Kd, whereas in a second case, the absence of correlation between ID and competitor activity, binding affinity, half-life of the peptides in serum, induction of proliferation in vitro and the individual immunogenicity of the peptides, suggested to us that ID of co-injected CTL epitopes can be determined both at the peptide level (binding affinity to H-2Kd) and at the T cell level. This hypothesis is supported by our finding that interleukin-12 strongly modulates ID when it is not correlated with MHC binding.


Subject(s)
Adjuvants, Immunologic/pharmacology , Immunodominant Epitopes/drug effects , Immunodominant Epitopes/pharmacology , Interleukin-12/immunology , Interleukin-12/pharmacology , T-Lymphocytes, Cytotoxic/immunology , Animals , Binding, Competitive/immunology , Drug Synergism , Female , H-2 Antigens/genetics , H-2 Antigens/immunology , HIV Envelope Protein gp120/immunology , HIV Envelope Protein gp120/pharmacology , HIV-1/immunology , Immunodominant Epitopes/administration & dosage , Injections, Intraperitoneal , Interleukin-12/administration & dosage , Mice , Mice, Inbred BALB C , Orthomyxoviridae/immunology , Protein Binding/immunology , Viral Core Proteins/immunology
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