Induction of apoptosis in mesothelioma cells by antisurvivin oligonucleotides

Mol Cancer Ther. 2002 Jul;1(9):687-94.


Malignant pleural mesothelioma is a rare and aggressive tumor characterized by rapid progression, late metastases, and poor prognosis. In this study, we investigated the expression of survivin, a member of the inhibitors of apoptosis protein gene family, in mesothelioma and an antisense oligonucleotide-based gene therapy for mesothelioma using survivin as a target. Initially, we documented the expression of survivin in human mesothelioma cell lines and fresh tissues using reverse transcription-PCR and Western blot analysis. Our results showed that survivin was overexpressed in 7 of 8 (87.5%) mesothelioma cell lines assayed and in all (12 of 12; 100%) freshly resected mesothelioma tissues analyzed. To investigate the use of survivin as a therapeutic target on mesothelioma, we carried out transfections with antisurvivin oligonucleotides to induce apoptosis in mesothelioma cell lines MS-1 and H28. Results from cellular transfection and subsequent analysis using the flow cytometry demonstrated that antisurvivin oligonucleotides induced significantly greater apoptosis rates in the survivin-positive mesothelioma cell line H28 (42.5%) as compared with the control oligonucleotides (16.2%; P < 0.001). The survivin-negative cell line LRK1A (survivin-/-) did not apoptose with antisense oligonucleotides. Furthermore, time course evaluation by Western blot analysis showed that survivin was inhibited by antisurvivin oligonucleotides within 12 h after transfection. Our results show, for the first time, that survivin, an inhibitors of apoptosis protein family gene member, is highly overexpressed in malignant pleural mesothelioma. Down-regulation of survivin by a targeted antisense oligonucleotide appears to be an effective gene therapy approach to the treatment of mesothelioma.

MeSH terms

  • Annexin A5 / pharmacology
  • Apoptosis*
  • Blotting, Western
  • Caspase 3
  • Caspases / metabolism
  • Cell Division
  • Cell Survival
  • DNA, Complementary / metabolism
  • Dose-Response Relationship, Drug
  • Down-Regulation
  • Flow Cytometry
  • Genetic Therapy*
  • Humans
  • Inhibitor of Apoptosis Proteins
  • Mesothelioma / pathology*
  • Mesothelioma / therapy*
  • Microtubule-Associated Proteins / genetics*
  • Microtubule-Associated Proteins / metabolism
  • Microtubule-Associated Proteins / pharmacology
  • Neoplasm Proteins
  • Oligonucleotide Array Sequence Analysis
  • Oligonucleotides / pharmacology*
  • Oligonucleotides, Antisense / pharmacology
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Survivin
  • Time Factors
  • Transfection
  • Tumor Cells, Cultured


  • Annexin A5
  • BIRC5 protein, human
  • DNA, Complementary
  • Inhibitor of Apoptosis Proteins
  • Microtubule-Associated Proteins
  • Neoplasm Proteins
  • Oligonucleotides
  • Oligonucleotides, Antisense
  • Proto-Oncogene Proteins c-bcl-2
  • Survivin
  • CASP3 protein, human
  • Caspase 3
  • Caspases