Reactive oxygen species induce apoptosis in selenite-treated colorectal cancer cells via PKD1/AKT signaling-mediated mitochondrial translocation of Bad
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Mounting evidence shows that supranutritional selenite-induced Reactive Oxygen Species (ROS) could trigger colorectal cancer (CRC) cells apoptosis, however, the molecular mechanism underlying this effect remains unclear. To explore the detailed mechanism how ROS induced apoptosis in selenite-treated CRC cells, we investigated the role of AKT/Bad signaling-mediated mitochondrial cell death in selenite-treated CRC cells and xenograft tumors. First, we found that selenite exposure inhibited Bad phosphorylation, leading to mitochondrial translocation of Bad, which further triggers HCT116 and SW480 CRC cells apoptosis. Furthermore, we identified that AKT-mediated phosphorylation shown to repress Bad function by causing it dissociate from mitochondria and bind to 14-3-3 proteins in the cytoplasm. Additionally, we discovered that selenite-induced ROS cause AKT dephosphorylation by inhibiting the kinase activity of protein kinase D1 (PKD1) in CRC cells. We also corroborated our findings in vivo by performing immunohistochemistry experiments. Overall, these observations demonstrate that ROS could induce apoptosis through promoting the mitochondrial translocation of Bad by inhibiting PKD1/AKT signaling in selenite-treated CRC cells in vitro and in vivo.
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