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ras oncogene expression determines sensitivity for intercellular induction of apoptosis
A Schwieger1, L Bauer, J Hanusch
1Abteilung Virologie, Institut für Medizinische Mikrobiologie und Hygiene, Universität Freiburg, Hermann-Herder Strasse 11, D-79104 Freiburg, Germany.
Abstract:
Fibroblasts carrying an inducible ras oncogene acquire the transformed phenotype after oncogene induction. As a consequence, the transformed cells become sensitive to intercellular induction of apoptosis, a novel regulatory process directed by non-transformed fibroblasts against their transformed descendants. The causal relationship between oncogene expression and sensitivity to intercellular induction of apoptosis is based on extracellular superoxide anion production by oncogene-expressing cells. Superoxide anions (after dismutation to hydrogen peroxide) thereby foster HOCl synthesis and at the same time direct the selectivity of apoptosis induction through hydroxyl generation from HOCl. In parallel, ras expression enhances the sensitivity of fibroblasts for apoptosis-inducing stimuli like cycloheximide, ceramide and mitomycin C. This sensitization seems to be based on a decreased concentration of short lived endogenous apoptosis inhibitors. TGF-beta, like ras induction, decreases the concentration of endogenous apoptosis inhibitors, but does not induce the transformed phenotype. Therefore, TGF-beta treatment alone is not sufficient to render fibroblasts sensitive for intercellular induction of apoptosis, but TGF-beta treatment in parallel with ras activation enhances intercellular induction of apoptosis. Our findings demonstrate that Ras-mediated superoxide anion production determines sensitivity to intercellular induction of apoptosis, whereas the parallel decrease in endogenous apoptosis inhibitors modulates the kinetics of apoptosis induction.
Insights
Fibroblasts with activated ras oncogenes become susceptible to apoptosis. Ras activation triggers superoxide anion production, leading to cell death, while also reducing apoptosis inhibitors.
Area of Science:
- Cell Biology
- Oncology
- Molecular Biology
Background:
- Fibroblasts acquire a transformed phenotype upon induction of a ras oncogene.
- Transformed cells exhibit sensitivity to intercellular apoptosis induction by non-transformed cells.
- This process represents a novel regulatory mechanism against transformed cells.
Purpose of the Study:
- To elucidate the molecular mechanisms linking ras oncogene expression to apoptosis sensitivity.
- To investigate the role of reactive oxygen species and endogenous inhibitors in this process.
- To understand the interplay between ras activation, TGF-beta, and apoptosis induction.
Main Methods:
- Utilized fibroblasts with an inducible ras oncogene.
- Analyzed extracellular superoxide anion production and reactive oxygen species (ROS) generation.
- Assessed changes in endogenous apoptosis inhibitors and sensitivity to apoptosis-inducing agents.
Main Results:
- Ras oncogene expression leads to extracellular superoxide anion production, crucial for apoptosis induction.
- Superoxide anions facilitate HOCl and hydroxyl radical generation, directing apoptosis.
- Ras activation decreases short-lived endogenous apoptosis inhibitors, enhancing sensitivity to stimuli like cycloheximide and ceramide.
- TGF-beta reduces apoptosis inhibitors but does not induce transformation; combined with ras, it enhances apoptosis induction.
Conclusions:
- Ras-mediated superoxide anion production is the primary determinant of sensitivity to intercellular apoptosis induction.
- The reduction in endogenous apoptosis inhibitors modulates the speed and efficiency of apoptosis.
- This study reveals a complex interplay between oncogene activation, ROS signaling, and apoptosis regulation in cancer.