STAT1 is overexpressed in tumors selected for radioresistance and confers protection from radiation in transduced sensitive cells.
Nu61, a radiation-resistant human tumor xenograft, was selected from a parental radiosensitive tumor SCC-61 by eight serial cycles of passage in athymic nude mice and in vivo irradiation. Replicate DNA array experiments identified 52 genes differentially expressed in nu61 tumors compared with SCC-61 tumors. Of these, 19 genes were in the IFN-signaling pathway and moreover, 25 of the 52 genes were inducible by IFN in the nu61 cell line. Among the genes involved in IFN signaling, STAT1alpha and STAT1beta were the most highly overexpressed in nu61 compared to SCC-61. STAT1alpha and STAT1beta cDNAs were cloned and stably transfected into SCC-61 tumor cells. Clones of SCC-61 tumor cells transfected with vectors expressing STAT1alpha and STAT1beta demonstrated radioprotection after exposure to 3 Gy (P < 0.038). The results indicate that radioresistance acquired during radiotherapy treatment may account for some treatment failures and demonstrate an association of acquired tumor radioresistance with up-regulation of components of the IFN-related signaling pathway.
Khodarev
Nikolai N
NN
Department of Radiation and Cellular Oncology, University of Chicago, 910 East 58th Street, Chicago, IL 60637, USA.
Beckett
Michael
M
Labay
Edwardine
E
Darga
Thomas
T
Roizman
Bernard
B
Weichselbaum
Ralph R
RR
D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D011836:Radiation Tolerance / Q000235:genetics*; D050794:STAT1 Transcription Factor; D012641:Selection, Genetic; D015534:Trans-Activators / Q000378:metabolism*; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C494080:Stat1 protein, mouse; D015534:Trans-Activators