Report on the research project with heavy ions at NIRS-HIMAC

Ionizing radiation (IR) has been shown to activate epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinase (ERK). EGFR activation by IR initiates the Ras/Raf/ERK signaling cascade, stimulates cell proliferation, and leads cells to be resistant to IR. The molecular mechanisms underlying IR-induced activation of EGFR are not clear. We have previously reported that IR-induced ERK1/2 activation involves EGFR through a Src-dependent pathway that is distinct from EGFR ligand activation. In the present study, we investigated the effects of carbon-beam on activities of ERK1/2, EGFR, and Src as indicated by their tyrosine phosphorylation and effects of AG1478 on them using human breast cancer cell line MDA-MB-468. Exposure of MDA-MB-468 cells to carbon-beam caused biphasic activation of ERK as indicated by its phosphorylation at Thr202/Tyr204. Irradiation with 0.001 Gy carbon-beam induced ERK1/2 activation, suggesting that bystander effect is involved in the carbon-beam-induced ERK1/2 activation. Inhibitors of nitric oxide synthase, 1400 W or L-NMMA did not inhibit carbon-beam-induced ERK1/2 activation. Inhibitor of gap junction, lindane did not inhibit carbon-beam-induced ERK1/2 activation. Effects of free radical scavenger on carbon-beam-induced ERK1/2 activation were investigated. α-tochopherol slightly suppressed the ERK1/2 activation, whereas ascorbic acid did not affect that. (author)