ROS signaling under metabolic stress: cross-talk between AMPK and AKT pathway

Abstract

Cancer cells are frequently confronted with metabolic stress in tumor microenvironments due to their rapid growth and limited nutrient supply. Metabolic stress induces cell death through ROS-induced apoptosis. However, cancer cells can adapt to it by altering the metabolic pathways. AMPK and AKT are two primary effectors in response to metabolic stress: AMPK acts as an energy-sensing factor which rewires metabolism and maintains redox balance. AKT broadly promotes energy production in the nutrient abundance milieu, but the role of AKT under metabolic stress is in dispute. Recent studies show that AMPK and AKT display antagonistic roles under metabolic stress. Metabolic stress-induced ROS signaling lies in the hub between metabolic reprogramming and redox homeostasis. Here, we highlight the cross-talk between AMPK and AKT and their regulation on ROS production and elimination, which summarizes the mechanism of cancer cell adaptability under ROS stress and suggests potential options for cancer therapeutics.

TXNIP regulates AKT‐mediated cellular senescence by direct interaction under glucose‐mediated metabolic stress

“…Recent reports have suggested that high glucose‐induced AKT signaling increases ROS levels by activating mTOR signaling, which induces glucose metabolism and protein synthesis, and by inhibiting FOXO signaling, which induces antioxidant gene transcription (Nogueira et al, 2008; Sheu et al, 2004). Consequently, AKT activation increases metabolic stress and ROS, resulting in a positive feedback loop that promotes cellular senescence (Dolado & Nebreda, 2008; Zhao et al, 2017). To investigate the activation of AKT in WT and KO MEF cells, we treated MEF cells with various concentrations of glucose or insulin, a peptide hormone that regulates glucose uptake, as a metabolic stress inducer.…”

“…KO mice exhibited greater AKT signaling, insulin sensitivity, and glycolysis in oxidative tissues than WT mice, which was associated with impaired mitochondrial fuel oxidation and the accumulation of oxidized PTEN (Hui et al, 2008). Intracellular ROS induce AKT activation, which in turn induces premature senescence by increasing ROS levels via inhibition of the transcriptional activity of the FOXO family and by activating mTOR pathways (Dolado & Nebreda, 2008; Johnson et al, 2013; Sheu et al, 2004; Zhao et al, 2017). Other groups also reported the function of AKT in aging.…”

Simultaneous Study of Mechanical Stretch-Induced Cell Proliferation and Apoptosis on C2C12 Myoblasts

“…Originally thought to be merely damaging byproducts of cell metabolism, ROS have recently been found to function as a signaling molecule that can activate cascades of signal transducers to address oxidative stress [Radak et al, 2013;Bigarella et al, 2014;Navarroyepes et al, 2014;Zhao et al, 2017]. Additionally, ROS may also oxidize or modify macromolecules, such as proteins, DNA, and lipids.…”

Metabolic networks in ferroptosis (Review)

“…NADPH, the predominant reducing agent in organisms, participates in a number of metabolic reactions. GSH is dehydrogenated to form glutathione disulfide, which is in turn reduced to GSH by glutathione reductase in the presence of NADPH (43). Given the functions of GSH, the synthesis of NADPH is important in resistance to peroxidation-induced damage during ferroptosis.…”