Phosphoinositide 3-Kinase/Akt Signaling and Redox Metabolism in Cancer

Abstract

Metabolic rewiring and the consequent production of reactive oxygen species (ROS) are necessary to promote tumorigenesis. At the nexus of these cellular processes is the aberrant regulation of oncogenic signaling cascades such as the phosphoinositide 3-kinase and AKT (PI3K/Akt) pathway, which is one of the most frequently dysregulated pathways in cancer. In this review, we examine the regulation of ROS metabolism in the context of PI3K-driven tumors with particular emphasis on four main areas of research. (1) Stimulation of ROS production through direct modulation of mitochondrial bioenergetics, activation of NADPH oxidases (NOXs), and metabolic byproducts associated with hyperactive PI3K/Akt signaling. (2) The induction of pro-tumorigenic signaling cascades by ROS as a consequence of phosphatase and tensin homolog and receptor tyrosine phosphatase redox-dependent inactivation. (3) The mechanisms through which PI3K/Akt activation confers a selective advantage to cancer cells by maintaining redox homeostasis. (4) Opportunities for therapeutically exploiting redox metabolism in PIK3CA mutant tumors and the potential for implementing novel combinatorial therapies to suppress tumor growth and overcome drug resistance. Further research focusing on the multi-faceted interactions between PI3K/Akt signaling and ROS metabolism will undoubtedly contribute to novel insights into the extensive pro-oncogenic effects of this pathway, and the identification of exploitable vulnerabilities for the treatment of hyperactive PI3K/Akt tumors.

In vivo hyperglycaemia exposure elicits distinct period‐dependent effects on human pancreatic progenitor differentiation, conveyed by oxidative stress

“…Interestingly, the AKT‐based signalling was linked to the energy metabolism pathways by our network analysis (Figure C). A large body of literature involved AKT2 either in a ROS‐stimulated positive feedback loop, promoting the glucose flux or in ROS signalling transduction, facilitating diverse ROS‐mediated changes in gene expression …”

“…A large body of literature involved AKT2 either in a ROS-stimulated positive feedback loop, promoting the glucose flux or in ROS signalling transduction, facilitating diverse ROS-mediated changes in gene expression. [25][26][27][28] Last, sectors of the observed proteome landscape reflected the inactivation of chromatin binders involved in differentiation regulation, such as the epigenetic modifier DNMT3B (methylase) and the oestrogen receptor alpha inhibitors SAFB2 and SAFB, involved in cell cycle/differentiation modulation in response to stress 29 ( Figure S2D). In contrast, SMARCA4, an ATP-dependent chromatin remodeler was predicted activated ( Figure S2B).…”

Hyperandrogenism and insulin resistance‐induced fetal loss: evidence for placental mitochondrial abnormalities and elevated reactive oxygen species production in pregnant rats that mimic the clinical features of polycystic ovary syndrome

“…While activation of the phosphoinositide 3‐kinase (PI3K)/Akt signalling pathway plays an important role in trophoblast function during pregnancy (Ferretti et al . ), aberrant regulation of this signalling pathway results in elevated ROS production (Koundouros & Poulogiannis, ). Although still speculative, our observations together with other findings suggest that the androgen–AR and insulin–insulin receptor–PI3K/Akt signalling pathways (Sferruzzi‐Perri et al .…”

Lactate Beyond a Waste Metabolite: Metabolic Affairs and Signaling in Malignancy

“…The major oncogene Ras, when mutated, can also induce glycolysis through the activation of the mammalian target of rapamycin complex I (mTORC1). Akt kinase activation by PI3K results in increased glucose uptake, HK2 targeting to the mitochondria, and increase in glycolytic flux (34), while the transcription factor MYC increases glutaminolysis and upregulates MCT1 expression (35). Cancer cell metabolism is also influenced by the activity of tumor suppressor genes.…”