The impact of oncogenic RAS on redox balance and implications for cancer development
Jonathan K M Lim1, Gabriel Leprivier2
1Institute for Neuropathology, Medical Faculty, Heinrich Heine University, Moorenstr. 5, 40225, Düsseldorf, Germany.
Abstract:
The RAS family of proto-oncogenes comprises HRAS, KRAS, and NRAS, which are among the most mutated genes in human cancers. The RAS family genes encode small GTPases that coordinate key signaling pathways in response to growth factors. Mutations in RAS result in a constitutively active form of the protein that supports cellular transformation and tumorigenesis. The mechanisms of oncogenic RAS-mediated transformation encompass uncontrolled proliferation and inhibition of cell death through overactivation of the RAF-MEK-ERK and the PI3K-AKT pathways, respectively. In addition, the control of redox balance by RAS has also been proposed to play a role in its oncogenic properties. However, the exact role of redox balance in mediating mutant RAS transformation is still under debate. Here, we present, on one hand, the involvement of pro-oxidant components in oncogenic RAS transformation, such as NADPH oxidases and mitochondrial reactive oxygen species, and how these promote transformation. On the other hand, we describe the contribution of antioxidant components to mutant RAS transformation, including Nrf2, glutathione biosynthesis and xCT, as well as the mechanisms by which antioxidant programs drive transformation. Finally, we aim to reconcile the seemingly opposite effects of oncogenic RAS on redox balance and discuss a model for the complementary role of both pro-oxidant and antioxidant pathways in mutant RAS-driven tumor progression.
Insights
Mutant RAS proteins drive cancer by promoting cell growth and survival. This study explores how both pro-oxidant and antioxidant pathways contribute to RAS-driven tumor progression, offering a new model for understanding this complex process.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- RAS family genes (HRAS, KRAS, NRAS) are frequently mutated in human cancers.
- Mutant RAS proteins lead to uncontrolled cell growth and survival, driving tumorigenesis.
- The role of cellular redox balance in RAS-mediated transformation is not fully understood.
Purpose of the Study:
- To investigate the dual role of pro-oxidant and antioxidant pathways in oncogenic RAS transformation.
- To elucidate the mechanisms by which these redox components promote or are utilized in cancer progression.
- To propose a model reconciling the seemingly contradictory effects of RAS on redox balance.
Main Methods:
- Review and synthesis of existing literature on RAS signaling and redox biology.
- Analysis of the involvement of NADPH oxidases, mitochondrial ROS, Nrf2, glutathione, and xCT in RAS-driven cancers.
- Discussion of proposed mechanisms for redox regulation in oncogenic transformation.
Main Results:
- Pro-oxidant factors like NADPH oxidases and mitochondrial reactive oxygen species (ROS) contribute to RAS transformation.
- Antioxidant systems, including Nrf2, glutathione biosynthesis, and xCT, are also crucial for mutant RAS-driven tumor progression.
- Both pro-oxidant and antioxidant pathways appear to play complementary roles in supporting tumor growth.
Conclusions:
- Oncogenic RAS utilizes both pro-oxidant and antioxidant mechanisms to facilitate cancer development.
- Understanding this redox balance is key to developing targeted cancer therapies.
- A model is proposed where both oxidative stress and antioxidant defense are essential for mutant RAS-driven tumorigenesis.
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