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Poly (ADP-ribose) polymerase activity regulates apoptosis in HeLa cells after alkylating DNA damage

Xuesong Liu1, Xu Luo, Yan Shi

  • 1Department R47S, Cancer Research, Abbott Laboratories, Abbott Park, Illinois 60064, USA. xuesong.liu@abbott.com

Cancer Biology & Therapy
|April 1, 2008
PubMed

Insights

The PARP inhibitor ABT-888 shifts N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) cell death from necrosis to apoptosis in HeLa cells by preserving ATP levels. This PARP inhibition determines cell fate after MNNG treatment.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Chemotherapeutic agents primarily induce tumor cell death via apoptosis or necrosis.
  • N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), a DNA alkylating agent, causes necrosis through DNA damage and poly(ADP-ribose) polymerase (PARP) over-activation.
  • PARP inhibition typically protects cells from MNNG-induced death.

Purpose of the Study:

  • To investigate the effect of the PARP inhibitor ABT-888 on MNNG-induced cell death in HeLa cells.
  • To elucidate the mechanism by which PARP inhibition influences cell fate following MNNG treatment.

Main Methods:

  • HeLa cells were treated with MNNG alone or in combination with ABT-888.
  • Cytochrome c release, Bcl-2 family protein expression, and ATP concentration were analyzed.
  • RNA interference (siRNA) and overexpression of Bcl-xl were used to study apoptosis regulation.
  • Oligomycin A was employed to assess the role of ATP in MNNG/ABT-888-induced apoptosis.

Main Results:

  • ABT-888 facilitated apoptotic cell death in MNNG-treated HeLa cells, unlike necrosis observed with MNNG alone.
  • Cytochrome c release occurred in both MNNG and MNNG/ABT-888 treatments, but apoptosis was only observed with the combination.
  • MNNG treatment drastically reduced ATP levels, while MNNG/ABT-888 treatment maintained ATP concentration.
  • Inhibition of ATP synthesis rendered cells resistant to MNNG/ABT-888-induced apoptosis.
  • ABT-888 protected normal human fibroblasts from MNNG-induced cell death.

Conclusions:

  • PARP activity is a critical determinant of cell fate (apoptosis vs. necrosis) in HeLa cells treated with MNNG.
  • Maintaining ATP levels via PARP inhibition is crucial for MNNG/ABT-888-induced apoptosis in HeLa cells.
  • The role of PARP inhibition in MNNG-induced cell death differs between cancer cells (HeLa) and normal cells (fibroblasts).

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