Transfection of Smac/DIABLO sensitizes drug-resistant tumor cells to TRAIL or paclitaxel-induced apoptosis in vitro

Pharmacol Res. 2007 Dec;56(6):483-92. doi: 10.1016/j.phrs.2007.09.010. Epub 2007 Sep 15.

Abstract

Smac/DIABLO is a recently identified protein released from mitochondria in response to apoptotic stimuli and promotes apoptosis by antagonizing inhibitor of apoptosis proteins (IAPs). In this study, we observed depressed Smac/DIABLO and increased XIAP expression in ovarian epithelial tissues ordered by normal, benign and malignant epithelia. In epithelial ovarian cancer (EOC), the expression of Smac/DIABLO decreased with the malignancy. Smac/DIABLO expression showed no correlation with TRAIL sensitivity, while lower Smac/DIABLO expression and decreased release of Smac/DIABLO from mitochondria upon apoptosis stimuli were observed in paclitaxel-resistant A2780/pac cells as compared to the sensitive controls. Ectopic Smac/DIABLO alone inhibited cell growth, arrested cells in G0/G1 phase, and sensitized drug-resistant EOC cells to TRAIL or paclitaxel-induced apoptosis. Increased apoptosis was associated with the down-regulation of XIAP, FLIP, and up-regulation of Smac/DIABLO, cytochrome c, p53, along with increased activity of caspase-3. Thus, over-expression of Smac/DIABLO is a promising strategy for drug-resistant ovarian cancer treatment.

MeSH terms

  • Adult
  • Antineoplastic Agents / pharmacology
  • Apoptosis
  • Apoptosis Regulatory Proteins
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm*
  • Female
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Middle Aged
  • Mitochondrial Proteins / genetics*
  • Mitochondrial Proteins / metabolism
  • Ovarian Neoplasms / genetics*
  • Ovarian Neoplasms / metabolism
  • Ovary / metabolism
  • Paclitaxel / pharmacology
  • RNA, Messenger / metabolism
  • TNF-Related Apoptosis-Inducing Ligand / pharmacology
  • Transfection
  • X-Linked Inhibitor of Apoptosis Protein / genetics
  • X-Linked Inhibitor of Apoptosis Protein / metabolism

Substances

  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • DIABLO protein, human
  • Intracellular Signaling Peptides and Proteins
  • Mitochondrial Proteins
  • RNA, Messenger
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • X-Linked Inhibitor of Apoptosis Protein
  • XIAP protein, human
  • Paclitaxel