Mechanism of heavy ion radiation-induced cancer cell death

We previously reported that the carbon beam triggers apoptosis in radio-resistant cancer cell lines. We therefore examined the apoptosis-inducing mechanism of carbon beam in two glioma cell lines (T98G, U251) by using caspase inhibitors, siRNA of Bax and Bak, and overexpression of Bcl-2 and Bcl-xl. We found that, in both T98G cell and U251 cell, multiple caspases including caspase-8 were activated downstream of mitochondria in Bcl-2-sensitive manner. Next, to investigate carbon beam-induced cell death signaling upstream of mitochondria, we examined possible involvement of stress kinase signaling in T98G cells. We noted dynamic change of ERK and P38 MAPK activities during the first 96 hrs of carbon beam irradiation. Pharmacological inhibition of ERK or P38 MAPKs reduced carbon beam-induced cell death. These data suggest that ERK and P38 MAPKs, as well as the mitochondrial pathway, play important roles in carbon beam-induced glioma cell death signaling. (author)