Nitric oxide promotes resistance to tumor suppression by CTLs.
Many human tumors express inducible NO synthetase (NOS2), but the roles of NO in tumor development are not fully elucidated. An important step during tumor development is the acquisition of apoptosis resistance. We investigated the dose-dependent effects of endogenously produced NO on apoptosis using ecdysone-inducible NOS2 cell lines. Our results show that short-term NOS2 expression enhances CD95-mediated apoptosis and T cell cytotoxicity dose dependently. Furthermore, we could show that during chronic exposure to NO, besides the primary cytotoxic NO effect, there is selection of cell clones resistant to NO that show cross-resistance to CD95-induced apoptosis and the killing by CTLs. We propose that NO production could initially act as an autocrine suicide or paracrine killing mechanism in cells undergoing malignant transformation. However, once failed, the outcome is fatal. NO promotes tumor formation by enhancing the selection of cells that can evade immune attack by acquiring apoptosis resistance.
Department of Internal Medicine, Johannes Gutenberg-University, Mainz, Germany.
Zhanhai
Z
Su
Jürgen
J
Kuball
Ana-Paula
AP
Barreiros
Daniela
D
Gottfried
Edite Antunes
EA
Ferreira
Matthias
M
Theobald
Peter R
PR
Galle
Dennis
D
Strand
Susanne
S
Strand
D017209:Apoptosis; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000378:metabolism; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D019014:fas Receptor / Q000378:metabolism
D019014:fas Receptor; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II