Intracellular reactive oxygen species are essential for PI3K/Akt/mTOR-dependent IL-7-mediated viability of T-cell acute lymphoblastic leukemia cells

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.

AMP-dependent kinase/mammalian target of rapamycin complex 1 signaling in T-cell acute lymphoblastic leukemia: therapeutic implications

“…The AMPK1/mTORC1 axis represents a recently identified promising therapeutic target in a number of tumors, as its activity is frequently deregulated in cancer cells. Constitutive activation of mTORC1 is a common event in T-ALL, 40 which emphasizes the potential of using mTORC1-targeting drugs as therapeutic agents in this disorder. In preclinical models of T-ALL, the efficacy of the mTORC1 inhibitor, rapamycin, appears weak, at least in monotherapy settings.…”

Cytotoxic activity of the novel Akt inhibitor, MK-2206, in T-cell acute lymphoblastic leukemia

“…All of the patients displayed enhanced phosphorylation of Ser 473 p-Akt (data not shown). T-ALL lymphoblast samples, cultured in the presence of IL-7, which functions as a powerful proliferative stimulus for these cells, 32,33 were treated with increasing concentrations of MK-2206, and cell survival was analyzed by MTT assays. A marked reduction in cell viability at 72 h was detected.…”

Targeting the PI3K/Akt/mTOR signaling pathway in B-precursor acute lymphoblastic leukemia and its therapeutic potential

“…The phosphatidylinositol 3-kinase (PI3K), Akt and the mammalian target of rapamycin (mTOR) (PI3K/Akt/mTOR) signaling pathway is frequently observed to be deregulated, thus leading to the pathogenesis of a variety of leukemias 4,5 including acute myeloid leukemia (AML), 6 T-cell ALL (T-ALL) 7 and B-pre ALL. 8 mTOR is a serine/threonine kinase, downstream of Akt, that controls cell proliferation and survival.…”