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Mitogenic signaling mediated by oxidants in Ras-transformed fibroblasts

K Irani1, Y Xia, J L Zweier

  • 1Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Science (New York, N.Y.)
|March 14, 1997
PubMed

Insights

Constitutively active H-RasV12 transforms cells, increasing reactive oxygen species (ROS) like superoxide. Antioxidants and inhibitors targeting Ras pathways, flavoproteins, and Rac1 suppressed ROS and cell growth, suggesting ROS mediation in Ras-induced transformation.

Area of Science:

  • Cell Biology
  • Biochemistry
  • Oncology

Background:

  • Ras proteins are key regulators of cell signaling pathways.
  • Aberrant Ras signaling is implicated in various cancers.
  • Reactive oxygen species (ROS) play complex roles in cell proliferation and transformation.

Purpose of the Study:

  • To investigate the role of reactive oxygen species (ROS) in H-RasV12-induced fibroblast transformation.
  • To identify the signaling pathways involved in ROS production downstream of H-RasV12.
  • To explore the potential of targeting ROS pathways as a therapeutic strategy against Ras-driven cancers.

Main Methods:

  • NIH 3T3 fibroblasts were stably transformed with H-RasV12.
  • Superoxide (.O2-) production was measured.
  • Dominant-negative Ras and Rac1 isoforms were expressed.
  • Cells were treated with farnesyltransferase inhibitor and diphenylene iodonium.
  • Mitogenic activity was assessed after N-acetyl-L-cysteine treatment.
  • Mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) activities were analyzed.

Main Results:

  • H-RasV12-transformed cells exhibited significantly increased superoxide (.O2-) production.
  • .O2- production was reduced by dominant-negative Ras/Rac1, farnesyltransferase inhibitor, and diphenylene iodonium.
  • Antioxidant treatment (N-acetyl-L-cysteine) inhibited the mitogenic activity of H-RasV12 cells.
  • MAPK activity was decreased, and JNK was not activated in H-RasV12-transformed cells.

Conclusions:

  • H-RasV12-induced cell transformation is associated with increased ROS production, specifically superoxide (.O2-).
  • Rac1 and flavoprotein-dependent pathways are involved in H-RasV12-mediated ROS generation.
  • Ras-induced cell cycle progression may be mediated by ROS independently of MAPK and JNK pathways, suggesting a novel therapeutic target for Ras-driven cancers.

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