p53-independent endoplasmic reticulum stress-mediated cytotoxicity of a Newcastle disease virus strain in tumor cell lines.
While Newcastle disease virus (NDV) causes serious infections in birds, it is apparently nonpathogenic in mammalian species, including humans. Previous observations and small-scale clinical trials indicated that NDV exerts oncolytic effects. Isolates of NDV were found to have selective affinity to transformed cells. We previously showed that the attenuated NDV strain MTH-68/H causes apoptotic cell death in cultures of PC12 rat pheochromocytoma cells. The aim of the present study was to extend MTH-68/H cytotoxicity testing with human tumor cell lines and to analyze certain biochemical aspects of its oncolytic effect. MTH-68/H was found to be able to kill a wide range of transformed cells by apoptosis. While caspase-8 and caspase-9 are not involved in MTH-68/H-induced apoptosis, activation of caspase-3 and caspase-12 was detected in virus-infected PC12 cells. A human glioblastoma cell line with repressible expression of the p53 protein did not show any difference in MTH-68/H sensitivity in its p53-expressing and p53-depleted states, indicating that the apoptotic process induced by MTH-68/H does not depend on p53. Apoptosis was accompanied by virus replication in two tumor cell lines tested (PC12 cells and HeLa human cervical cells), and signs of endoplasmic reticulum stress (phosphorylation of protein kinase R-like endoplasmic reticulum kinase and eIF2alpha) were also detected in transformed cells. In contrast, proliferation of nontransformed mouse and rat fibroblast cell lines and human primary fibroblasts was not affected by MTH-68/H treatment. MTH-68/H thus selectively kills tumor cell cultures by inducing endoplasmic reticulum stress leading to p53-independent apoptotic cell death.
Fábián
Zsolt
Z
Department of Medical Biology, Medical School, University of Pécs, H-7624 Pécs, Szigeti 12, Hungary.
Csatary
Christine M
CM
Szeberényi
József
J
Csatary
Laszlo K
LK
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D017209:Apoptosis; D002277:Carcinoma / Q000473:pathology; D053454:Caspase 12 / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002472:Cell Transformation, Viral / Q000502:physiology*; D004721:Endoplasmic Reticulum / Q000502:physiology*; D004789:Enzyme Activation; D005260:Female; D005909:Glioblastoma / Q000473:pathology; D045325:HCT116 Cells; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D009522:Newcastle disease virus / Q000235:genetics / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology*; D016716:PC12 Cells; D010190:Pancreatic Neoplasms / Q000473:pathology; D051381:Rats; D013752:Tetracycline / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D014779:Virus Replication
D000900:Anti-Bacterial Agents; D016159:Tumor Suppressor Protein p53; D053454:Caspase 12; D053148:Caspase 3; D013752:Tetracycline