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Expression of Smac/DIABLO in ovarian carcinoma cells induces apoptosis via a caspase-9-mediated pathway

I A McNeish1, S Bell, T McKay

  • 1Cancer Research UK Molecular Oncology Unit, Imperial College School of Medicine, Hammersmith Hospital, W12 ONN, London, UK. iain.mcneish@cancer.org.uk

Experimental Cell Research
|May 17, 2003
PubMed

Insights

We engineered a virus to deliver Smac/DIABLO, a protein that triggers programmed cell death (apoptosis). This virus effectively induced apoptosis in ovarian cancer cells, offering a potential new cancer therapy.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Oncology

Background:

  • Smac/DIABLO is a mitochondrial protein that promotes apoptosis by antagonizing inhibitors of apoptosis proteins.
  • Recombinant adenoviruses are effective vectors for gene delivery in cancer therapy.

Purpose of the Study:

  • To construct and evaluate a recombinant adenovirus encoding Smac/DIABLO (Ad CMV-Smac) for its ability to induce apoptosis in ovarian carcinoma cells.
  • To elucidate the apoptotic pathway activated by Ad CMV-Smac.

Main Methods:

  • Construction of Ad CMV-Smac, a recombinant adenovirus encoding Smac/DIABLO.
  • Transfection of ovarian carcinoma cells with Ad CMV-Smac at varying multiplicities of infection.
  • Western blot analysis to assess caspase activation and apoptosis markers.
  • Inhibition studies using zLEHD-fmk and XIAP overexpression.

Main Results:

  • Ad CMV-Smac induced apoptosis in ovarian carcinoma cells in a dose-dependent manner.
  • Smac-induced apoptosis was mediated primarily by caspase-9 and could be inhibited by zLEHD-fmk and XIAP.
  • Apoptosis was independent of cytochrome c release and Bcl-2 overexpression.
  • Ad CMV-Smac enhanced apoptosis when combined with cisplatin, paclitaxel, or procaspase-3.

Conclusions:

  • Ad CMV-Smac is a potent inducer of apoptosis in ovarian cancer cells via a caspase-9-dependent pathway.
  • Smac/DIABLO delivery using adenovirus shows promise as a therapeutic strategy for ovarian cancer, potentially in combination with other agents.

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