Impacts of Oxidative Stress and PI3K/AKT/mTOR on Metabolism and the Future Direction of Investigating Fucoidan-Modulated Metabolism

Abstract

The critical factors for regulating cancer metabolism are oxidative stress and phosphoinositide-3-kinase/AKT serine-threonine kinase/mechanistic target of the rapamycin kinase (PI3K/AKT/mTOR). However, the metabolic impacts of oxidative stress and PI3K/AKT/mTOR on individual mechanisms such as glycolysis (Warburg effect), pentose phosphate pathway (PPP), fatty acid synthesis, tricarboxylic acid cycle (TCA) cycle, glutaminolysis, and oxidative phosphorylation (OXPHOS) are complicated. Therefore, this review summarizes the individual and interacting functions of oxidative stress and PI3K/AKT/mTOR on metabolism. Moreover, natural products providing oxidative stress and PI3K/AKT/mTOR modulating effects have anticancer potential. Using the example of brown algae-derived fucoidan, the roles of oxidative stress and PI3K/AKT/mTOR were summarized, although their potential functions within diverse metabolisms were rarely investigated. We propose a potential application that fucoidan may regulate oxidative stress and PI3K/AKT/mTOR signaling to modulate their associated metabolic regulations. This review sheds light on understanding the impacts of oxidative stress and PI3K/AKT/mTOR on metabolism and the future direction of metabolism-based cancer therapy of fucoidan.

Keywords: AKT; PI3K; anticancer; fucoidan; mTOR; metabolism; oxidative stress.

Figure 1

Oxidative stress and its associated metabolisms. Arrow indicates activation; T indicates inhibition; T with arrow indicates inhibition leading to activation. Abbreviations: PPP, pentose phosphate pathway; TCA, tricarboxylic acid cycle; FA, fatty acid; OXPHOS, oxidative phosphorylation. These effects are summarized in the reports mentioned in Section 2.1, Section 2.2, Section 2.3, Section 2.4, Section 2.5, Section 2.6. Different studies reported differential regulations to these metabolisms by modulating oxidative stress. Various reports show different responses to oxidative stress for the same metabolism.

Figure 2

PI3K/AKT/mTOR signaling regulates metabolisms of glycolysis, PPP, nucleotide synthesis, lipid synthesis, TCA cycle, glutaminolysis, and OXPHOS. Solid and blank boxes indicate activation and inactivation by AKT. Abbreviations: G, glucose; G6P, glucose-6-phosphate; F6P, fructose-6-phosphate; F1,6BP, fructose-1,6-bisphosphate; HK, hexokinase; PFK1, phosphofructokinase 1; PDH, pyruvate dehydrogenase; PDK1, pyruvate dehydrogenase kinase 1; α-KG, α-ketoglutarate; TCA, tricarboxylic acid cycle; OXPHOS, oxidative phosphorylation.

Figure 3

Relationship between AKT signaling, target enzymes, and their affected metabolisms. Abbreviations: FOXO, forkhead box transcription factors; HIF, hypoxia-inducible factor; mTORC1, mechanistic target of rapamycin complex 1; S6K1, mTOR substrate S6 kinase 1; sterol regulatory element-binding transcription factor 1; SREBP1; HK, hexokinase; PFK1/2, phosphofructokinase 1/2; PDK1, pyruvate dehydrogenase kinase 1; LDH, lactate dehydrogenase; PDH, pyruvate dehydrogenase; PPP, pentose phosphate pathway.

Figure 4

PI3K/AKT/mTOR and its associated metabolisms. Arrows indicate activation; T indicates inhibition; T with an arrow indicates PI3K/AKT/mTOR inhibition leading to metabolic activation. Abbreviations: PPP, pentose phosphate pathway; TCA, tricarboxylic acid cycle; FA, fatty acid; OXPHOS, oxidative phosphorylation. These effects were summarized from the reports mentioned in Section 3.1, Section 3.2, Section 3.3, Section 3.4, Section 3.5, Section 3.6. Different studies reported differential regulations to these metabolisms by modulating PI3K/AKT/mTOR signaling. Various reports show different PI3K/AKT/mTOR responses for the same metabolism.

Figure 5

Interaction between oxidative stress and PI3K/AKT/mTOR. Oxidative stress and PI3K/AKT/mTOR can reciprocally induce or suppress each other. The antioxidant system also regulates oxidative stress.

Figure 6

Hypothesis. Fucoidan may modulate oxidative stress and PI3K/AKT/mTOR in metabolic regulations. Oxidative stress and PI3K/AKT/mTOR can reciprocally induce or suppress each other. The antioxidant system also regulates oxidative stress. Fucoidan can modulate oxidative stress and PI3K/AKT/mTOR, but their impacts on fucoidan-modulated metabolisms are rarely investigated. Accordingly, fucoidan may trigger oxidative stress and PI3K/AKT/mTOR to control several metabolic functions. Abbreviations: PPP, pentose phosphate pathway; TCA, tricarboxylic acid cycle; FA, fatty acid; OXPHOS, oxidative phosphorylation.