Cadmium, one of toxic heavy metals, may be accumulated in the body through long-term exposure to cadmium-polluted environment, which contributes to carcinogenesis, immunodepression and neurodegeneration. To study the mechanism of cadmium-induced neurodegeneration, PC12 and SH-SY5Y cells were exposed to cadmium. We observed that cadmium induced apoptosis of the cells in a time- and concentration-dependent manner. Cadmium rapidly activated Erk1/2 and JNK. Treatment of cells with U0126, an MEK1/2 (upstream of Erk1/2) inhibitor, or SP600125, a JNK inhibitor, inhibited cadmium-induced phosphorylation of Erk1/2 and JNK, respectively, and partially rescued cells from cadmium-induced apoptosis. To our surprise, cadmium also activated mTOR-mediated S6K1 and 4E-BP1 pathways. Treatment with rapamycin, an mTOR inhibitor, inhibited cadmium-induced phosphorylation of S6K1 and 4E-BP1, but did not affect phosphorylation of Erk1/2 and c-Jun, a substrate of JNK. Rapamycin also partially prevented cadmium-induced apoptosis. We also noticed that N-acetyl-L-cystein (NAC), an antioxidant, prevented cadmium-induced cell death and blocked activation of mTOR, Erk1/2, and JNK, suggesting that cadmium induced generation of reactive oxygen species (ROS), which may trigger cellular stress responses.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA