Role of TGF-beta1 and nitric oxide in the bystander response of irradiated glioma cells.
The radiation-induced bystander effect (RIBE) increases the probability of cellular response and therefore has important implications for cancer risk assessment following low-dose irradiation and for the likelihood of secondary cancers after radiotherapy. However, our knowledge of bystander signaling factors, especially those having long half-lives, is still limited. The present study found that, when a fraction of cells within a glioblastoma population were individually irradiated with helium ions from a particle microbeam, the yield of micronuclei (MN) in the nontargeted cells was increased, but these bystander MN were eliminated by treating the cells with either aminoguanidine (an inhibitor of inducible nitric oxide (NO) synthase) or anti-transforming growth factor beta1 (anti-TGF-beta1), indicating that NO and TGF-beta1 are involved in the RIBE. Intracellular NO was detected in the bystander cells, and additional TGF-beta1 was detected in the medium from irradiated T98G cells, but it was diminished by aminoguanidine. Consistent with this, an NO donor, diethylamine nitric oxide (DEANO), induced TGF-beta1 generation in T98G cells. Conversely, treatment of cells with recombinant TGF-beta1 could also induce NO and MN in T98G cells. Treatment of T98G cells with anti-TGF-beta1 inhibited the NO production when only 1% of cells were targeted, but not when 100% of cells were targeted. Our results indicate that, downstream of radiation-induced NO, TGF-beta1 can be released from targeted T98G cells and plays a key role as a signaling factor in the RIBE by further inducing free radicals and DNA damage in the nontargeted bystander cells.
Shao
C
C
Gray Cancer Institute, Mount Vernon Hospital, Northwood, Middlesex, UK.
Folkard
M
M
Prise
K M
KM
D024201:Bystander Effect / Q000528:radiation effects*; D004249:DNA Damage; D005609:Free Radicals / Q000378:metabolism / Q000528:radiation effects; D005910:Glioma / Q000235:genetics / Q000532:radiotherapy*; D006801:Humans; D048629:Micronuclei, Chromosome-Defective / Q000528:radiation effects; D008954:Models, Biological; D009569:Nitric Oxide / Q000502:physiology*; D015398:Signal Transduction / Q000528:radiation effects; D053773:Transforming Growth Factor beta1 / Q000502:physiology*; D014407:Tumor Cells, Cultured
D005609:Free Radicals; D053773:Transforming Growth Factor beta1; D009569:Nitric Oxide