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ROS, stress-activated kinases and stress signaling in cancer
Moran Benhar1, David Engelberg, Alexander Levitzki
1Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
Abstract:
Anticancer therapy is frequently efficient in early stages of the disease, whereas advanced tumors are usually resistant to the same treatments. The molecular basis for this change is not entirely understood. Many anticancer agents are DNA- or cytoskeleton-damaging drugs that show some specificity towards dividing cells. However, recent studies show that these agents also activate stress-signaling cascades that may play a role in eliciting the observed therapeutic effects. We discuss recent findings that suggest that induction of stress signaling in oncogenically transformed cells is integrated into apoptotic pathways. Reactive oxygen species (ROS) and stress-activated protein kinases (SAPKs), which are potentiated in recently transformed cells, emerge as key effectors of cell death. In advanced tumors, however, these agents are downregulated and, consequently, death signaling is suppressed. Such changes in ROS and SAPK activity levels during the course of tumor development may underlie the changes in responsiveness to anticancer therapy.
Insights
Anticancer therapy works best in early stages because stress signaling pathways, involving reactive oxygen species (ROS) and stress-activated protein kinases (SAPKs), promote cancer cell death. In advanced tumors, these pathways are suppressed, leading to treatment resistance.
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- Anticancer therapies are often effective in early-stage cancers but less so in advanced tumors.
- The molecular mechanisms driving this differential response remain incompletely understood.
- Standard anticancer drugs target DNA or the cytoskeleton, primarily affecting dividing cells.
Purpose of the Study:
- To investigate the role of stress-signaling cascades in mediating anticancer therapy effects.
- To explore how these signaling pathways change during tumor progression and impact treatment response.
- To elucidate the molecular basis for acquired resistance to anticancer agents.
Main Methods:
- Review of recent findings on stress signaling in cancer.
- Analysis of the role of reactive oxygen species (ROS) and stress-activated protein kinases (SAPKs).
- Correlation of signaling pathway activity with tumor stage and therapeutic outcomes.
Main Results:
- Stress-signaling cascades, including ROS and SAPKs, are activated by anticancer agents.
- These activated pathways are integrated into apoptotic (programmed cell death) pathways in transformed cells.
- In advanced tumors, ROS and SAPK activity is downregulated, suppressing cell death signaling.
Conclusions:
- The induction of stress signaling is crucial for the efficacy of anticancer therapy in early-stage disease.
- Downregulation of ROS and SAPK activity in advanced tumors contributes to therapeutic resistance.
- Modulating stress-signaling pathways may offer strategies to overcome treatment resistance in advanced cancers.