thapsigargin and Adenocarcinoma--Clear-Cell

The prostate-apoptosis-response-gene-4 (Par-4) protein has been shown to function as an effector of cell death in response to various apoptotic stimuli that trigger mitochondria and membrane receptor-mediated cell death pathways. We found that overexpressing Par-4 by stable transfection sensitizes Caki cells to induction of apoptosis by TRAIL and drugs that induce endoplasmic reticulum (ER) stress [thapsigargin (TG), tunicamycin (TU) and etoposide]. Ectopic expression of Par-4 is associated with decreased levels of XIAP protein in TG-treated cells, caused in part by XIAP protein instability and caspase activation. Levels of phospho-Akt are decreased in Caki/Par-4 cells to a significantly greater extent than in Caki/Vector cells by treatment with TG, and this is in turn associated with decreased levels of phospho-PDK1, the kinase upstream of Akt. In conclusion, we provide evidence that ectopic expression of Par-4 sensitizes Caki cells to TG and that XIAP protein instability and inactivation of Akt are important in cellular pathways affected by Par-4.

Topics: Adenocarcinoma, Clear Cell; Amino Acid Chloromethyl Ketones; Apoptosis; Apoptosis Regulatory Proteins; Caspases; Cell Division; Cell Line, Tumor; Endoplasmic Reticulum; Enzyme Activation; Etoposide; Gene Expression Regulation, Neoplastic; Humans; Kidney Neoplasms; Phosphorylation; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Pyruvate Dehydrogenase Acetyl-Transferring Kinase; Recombinant Fusion Proteins; Thapsigargin; TNF-Related Apoptosis-Inducing Ligand; Transfection; X-Linked Inhibitor of Apoptosis Protein