Overexpression of Par-4 enhances thapsigargin-induced apoptosis via down-regulation of XIAP and inactivation of Akt in human renal cancer cells

J Cell Biochem. 2008 Feb 1;103(2):358-68. doi: 10.1002/jcb.21642.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma, Clear Cell / pathology*
  • Amino Acid Chloromethyl Ketones / pharmacology
  • Apoptosis / drug effects*
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / physiology*
  • Caspases / metabolism
  • Cell Division / drug effects
  • Cell Line, Tumor / drug effects
  • Endoplasmic Reticulum / metabolism
  • Enzyme Activation / drug effects
  • Etoposide / pharmacology
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Kidney Neoplasms / pathology*
  • Phosphorylation / drug effects
  • Protein Processing, Post-Translational / drug effects
  • Protein Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • Recombinant Fusion Proteins / physiology
  • TNF-Related Apoptosis-Inducing Ligand / pharmacology
  • Thapsigargin / pharmacology*
  • Transfection
  • X-Linked Inhibitor of Apoptosis Protein / genetics
  • X-Linked Inhibitor of Apoptosis Protein / metabolism

Substances

  • Amino Acid Chloromethyl Ketones
  • Apoptosis Regulatory Proteins
  • PDK1 protein, human
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • Recombinant Fusion Proteins
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • X-Linked Inhibitor of Apoptosis Protein
  • XIAP protein, human
  • benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
  • prostate apoptosis response-4 protein
  • Thapsigargin
  • Etoposide
  • AKT1 protein, human
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Caspases