DATS increased p66Shc phosphorylation at serine 36, which was abolished by JNK inhibitor, and DATS-induced ROS formation was abolished in cells expressing p66ShcS36A variant. In cells expressing this variant, DATS-induced Akt dephosphorilation was reduced. The signaling pathway with P66Shc could be indispensable for DATS-induced prostate cancer cell death by modulating the Akt activity and ROS generation. The gene discussed is MAPK8; the disease is prostate cancer.