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PI3K inhibitors changed the p53-induced response of Saos-2 cells from growth arrest to apoptosis

Shuo Ren1, ChongFeng Gao, Lilin Zhang

  • 1Department of Molecular Cellular Oncology and Microbiology, Graduate School of Medicine and Dentistry, Tokyo Medical Dental University, Bunkyo-ku, Tokyo 113-8549, Japan.

Biochemical and Biophysical Research Communications
|August 2, 2003
PubMed

Insights

Blocking PI3K/Akt survival signals with inhibitors like LY294002 induces apoptosis in cancer cells arrested by p53. This research clarifies the cell fate decision between growth arrest and programmed cell death.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • The tumor suppressor protein p53 plays a crucial role in cell cycle regulation and apoptosis following oncogenic stress.
  • The precise mechanisms governing p53's decision between cell cycle arrest and apoptosis remain incompletely understood.
  • Saos-2 cells with temperature-sensitive p53 were utilized to study cell fate decisions under controlled conditions.

Purpose of the Study:

  • To investigate the role of the PI3K/Akt pathway in mediating the cellular response to p53 activation.
  • To determine if inhibiting PI3K/Akt signaling can redirect growth-arrested cells towards apoptosis.
  • To elucidate the molecular pathways involved in this cell fate determination.

Main Methods:

  • Utilized Saos-2 cells with temperature-sensitive wild-type p53, growth-arrested in G1 and G2/M phases.
  • Administered PI3K/Akt inhibitors (LY294002, wortmannin) and a MEK inhibitor (U0126).
  • Assessed apoptosis through sub-G1 DNA content, nuclear morphology, DNA laddering, caspase cleavage, PARP cleavage, cytochrome c release, and Bax translocation.

Main Results:

  • PI3K/Akt inhibitors LY294002 and wortmannin induced apoptosis in growth-arrested Saos-2 cells.
  • Apoptosis induction was characterized by increased sub-G1 population, pyknotic nuclei, and DNA fragmentation.
  • LY294002 treatment led to caspase-9, caspase-3 cleavage, PARP cleavage, mitochondrial cytochrome c release, and Bax translocation, with decreased phospho-Akt levels.

Conclusions:

  • The PI3K/Akt pathway is critical in determining cell fate between growth arrest and apoptosis.
  • Inhibiting PI3K/Akt signaling effectively triggers apoptosis via the mitochondrial pathway in p53-arrested cells.
  • Blocking survival signals disrupts the balance, promoting programmed cell death.

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