Antisense to SV40 early gene region induces growth arrest and apoptosis in T-antigen-positive human pleural mesothelioma cells.
Although SV40 oncoproteins have been detected in malignant pleural mesotheliomas (MPMs), their role in the pathogenesis and clinical behavior of these neoplasms remains controversial. In the present study, we sought to define the relevance of SV40 T/t antigen expression in established human mesothelioma cell lines deficient for p16INK4a as well as ARF expression. SV40 early region sequences were readily detected in genomic DNA isolated from pleural mesothelioma lines; however, levels of SV40 T/t antigen expression were highly variable in these cells. An adenoviral vector expressing an antisense transcript to SV40 early region inhibited T antigen expression and mediated significant growth inhibition and apoptosis in T-antigen-positive mesothelioma cells and SV40-transformed COS-7 cells. Abrogation of T/t antigen expression coincided with enhanced p21/WAF-1 expression, suggesting that restoration of p53-mediated pathways may have contributed to the growth inhibition and apoptosis induced by the antisense construct. These effects were not observed after similar treatment of mesothelioma or lung cancer cells containing no SV40 DNA sequences. Collectively, these data suggest that SV40 oncoproteins contribute to the malignant phenotype of pleural mesotheliomas and indicate that interventions designed to abrogate their expression may be efficacious in the treatment of individuals with these neoplasms.
Waheed
I
I
Thoracic Oncology Section, Surgery Branch, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
Guo
Z S
ZS
Chen
G A
GA
Weiser
T S
TS
Nguyen
D M
DM
Schrump
D S
DS
D000256:Adenoviridae / Q000235:genetics; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics*; D017209:Apoptosis; D002455:Cell Division / Q000187:drug effects; D018014:Gene Transfer Techniques; D017781:Genes, Immediate-Early; D005814:Genes, Viral; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008654:Mesothelioma / Q000188:drug therapy* / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D015513:Oncogene Proteins / Q000502:physiology; D010641:Phenotype; D010997:Pleural Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D013539:Simian virus 40 / Q000235:genetics*; D014407:Tumor Cells, Cultured
D000952:Antigens, Polyomavirus Transforming; D016376:Oligonucleotides, Antisense; D015513:Oncogene Proteins