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Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
09:18

Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death

Published on: December 27, 2016

Induction of prosurvival molecules by apoptotic stimuli: involvement of FOXO3a and ROS

Jun-Wei Liu1, Dhyan Chandra, Michael D Rudd

  • 1Department of Carcinogenesis, the University of Texas MD Anderson Cancer Center, Science Park-Research Division 1C, Smithville, TX 78957, USA.

Oncogene
|January 28, 2005
PubMed

Insights

Cancer cells resist apoptosis by upregulating prosurvival molecules like Bcl-2/Bcl-X(L) and superoxide dismutase (SOD). This survival mechanism, activated by reactive oxygen species (ROS) and transcription factor FOXO3a, hinders cancer therapeutics.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Cancer therapeutics often fail due to rapid development of resistance by cancer cells to proapoptotic effects.
  • The precise mechanisms underlying this resistance are not fully understood.
  • Identifying these mechanisms is crucial for developing more effective cancer treatments.

Purpose of the Study:

  • To investigate the rapid induction of prosurvival molecules in response to apoptotic stimuli.
  • To elucidate the role of transcription factor FOXO3a and reactive oxygen species (ROS) in this process.
  • To explore potential strategies for overcoming therapeutic resistance in cancer.

Main Methods:

  • Induction of apoptosis using serum starvation, a mitochondrial toxin, and etoposide.
  • Analysis of prosurvival (Bcl-2/Bcl-X(L), SOD) and proapoptotic (Bim, Bak) molecule expression.
  • Utilized siRNAs to block molecule induction and assess effects on apoptosis.
  • Investigated the role of transcription factor FOXO3a and ROS using inhibitors/scavengers.

Main Results:

  • Apoptotic stimuli rapidly induced prosurvival molecules (Bcl-2/Bcl-X(L), SOD) before or concurrently with proapoptotic molecules (Bim, Bak).
  • FOXO3a was identified as a master transcription factor involved in regulating both prosurvival and proapoptotic molecules, and was itself upregulated.
  • Reactive oxygen species (ROS) were rapidly induced and found to mediate the upregulation of FOXO3a, MnSOD, and Bim.
  • Prosurvival mechanisms were also activated in normal fibroblasts and at subapoptotic concentrations.

Conclusions:

  • Apoptotic stimuli rapidly activate prosurvival mechanisms via ROS-dependent pathways involving transcription factor FOXO3a.
  • Cancer cells and normal cells mobilize survival strategies in response to apoptotic triggers.
  • Effective anticancer therapeutics may require combined strategies targeting both apoptosis induction and survival suppression.

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