Intracellular reactive oxygen species are essential for PI3K/Akt/mTOR-dependent IL-7-mediated viability of T-cell
1Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
Abstract:
Interleukin-7 (IL-7) activates phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway, thereby mediating viability, proliferation and growth of T-cell acute lymphoblastic leukemia (T-ALL) cells. Reactive oxygen species (ROS) can be upregulated by growth factors and are known to regulate proliferation and viability. Here, we show that IL-7 upregulates ROS in T-ALL cells in a manner that is dependent on PI3K/Akt/mTOR pathway activity and that relies on both NADPH oxidase and mitochondrial respiratory chain. Conversely, IL-7-induced activation of PI3K signaling pathway requires mitochondrial respiration and ROS. We have previously shown that IL-7-mediated activation of PI3K pathway drives the upregulation of the glucose transporter Glut1, promoting glucose uptake in T-ALL cells. Using phloretin to inhibit Glut function, we demonstrate that glucose uptake is mandatory for ROS upregulation in IL-7-treated T-ALL cells, suggesting that IL-7 stimulation leads to increased ROS via PI3K pathway activation and consequent upregulation of Glut1 and glucose uptake. Overall, our data reveal the existence of a critical crosstalk between PI3K/Akt signaling pathway and ROS that is essential for IL-7-mediated T-ALL cell survival, and that may constitute a novel target for therapeutic intervention.
Insights
Interleukin-7 (IL-7) signaling promotes T-cell acute lymphoblastic leukemia (T-ALL) survival by increasing reactive oxygen species (ROS) through the PI3K/Akt/mTOR pathway and glucose uptake. This pathway crosstalk presents a potential therapeutic target for T-ALL.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Signaling
Background:
- Interleukin-7 (IL-7) is crucial for T-cell development and survival.
- The phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway regulates cell viability and proliferation.
- T-cell acute lymphoblastic leukemia (T-ALL) cells rely on IL-7 for survival.
Purpose of the Study:
- To investigate the role of reactive oxygen species (ROS) in IL-7-mediated T-ALL cell survival.
- To elucidate the relationship between IL-7 signaling, ROS production, and glucose metabolism in T-ALL.
Main Methods:
- Analysis of ROS production in T-ALL cells stimulated with IL-7.
- Assessment of PI3K/Akt/mTOR pathway activity and its dependence on ROS and mitochondrial respiration.
- Inhibition of glucose transporter (Glut) function using phloretin to evaluate its impact on ROS upregulation.
Main Results:
- IL-7 upregulates ROS in T-ALL cells via PI3K/Akt/mTOR pathway activation, involving NADPH oxidase and mitochondrial respiration.
- IL-7-induced PI3K activation requires mitochondrial respiration and ROS.
- Glucose uptake, mediated by Glut1 upregulation, is essential for IL-7-induced ROS production in T-ALL cells.
Conclusions:
- A critical crosstalk exists between the PI3K/Akt signaling pathway and ROS in IL-7-mediated T-ALL cell survival.
- This interplay involves IL-7-driven PI3K activation, subsequent Glut1 upregulation, increased glucose uptake, and ROS generation.
- The identified signaling axis represents a potential novel therapeutic target for T-ALL treatment.
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