The Role of Akt Pathway Signaling in Glucose Metabolism and Metabolic Oxidative Stress

Simons, Andrean L.; Orcutt, Kevin P.; Madsen, Joshua; Scarbrough, Peter M.; Spitz, Douglas R.

doi:10.1007/978-1-61779-397-4_2

Cited by 20 publications

(22 citation statements)

References 114 publications

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“…1A). To study the underlying signaling pathway(s) that mediate(s) this increase, we tested the effect of insulin, which activates PI3K-Akt signaling, similarly to high glucose (19, 32). Treatment of NMuMG cells or MEFs with insulin induced rapid increases in the TβRI and TβRII abundance at the plasma membrane, without changes in their total abundance (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Because high glucose induces Akt activation (19), we asked whether insulin, which also activates the PI3K-Akt pathway and controls glucose homeostasis (20, 21), regulates the cell surface abundance of TGF-β receptors. Insulin is a small polypeptide hormone that is released by pancreatic beta cells and induces glucose uptake by mobilizing glucose transporters from intracellular stores to the cell membrane, thus lowering the glucose levels in blood (22, 23).…”

Section: Introductionmentioning

confidence: 99%

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The insulin response integrates increased TGF-β signaling through Akt-induced enhancement of cell surface delivery of TGF-β receptors

2015

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Increased activity of transforming growth factor β (TGF-β), which binds to and stimulates cell surface receptors, contributes to cancer progression and fibrosis by driving epithelial cells toward a migratory mesenchymal phenotype and increasing the abundance of extracellular matrix proteins. The abundance of TGF-β receptors at the cell surface determines cellular responsiveness to TGF-β, which is often produced by the same cells that have the receptors, and thus serves as an autocrine signal. We found that Akt-mediated phosphorylation of AS160, a RabGAP [guanosine triphosphatase (GTPase)-activating protein] promoted the translocation of TGF-β receptors from intracellular stores to the plasma membrane of mouse embryonic fibroblasts (MEFs) and NMuMG epithelial cells. Consequently, insulin, which is commonly used to treat hyperglycemia and activates Akt signaling, increased the amount of TGF-β receptors at the cell surface, thereby enhancing TGF-β responsiveness. This insulin-induced increase in autocrine TGF-β signaling contributed to insulin-induced gene expression responses, attenuated the epithelial phenotype, and promoted the migration of NMuMG cells. Furthermore, the enhanced delivery of TGF-β receptors at the cell surface enabled insulin to increase TGF-β-induced gene responses. The enhancement of TGF-β responsiveness in response to Akt activation may help to explain the biological effects of insulin, the progression of cancers in which Akt is activated, and the increased incidence of fibroses in diabetes.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The insulin response integrates increased TGF-β signaling through Akt-induced enhancement of cell surface delivery of TGF-β receptors

2015

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“…The AKT/mTOR pathway is involved in transcription of anti-apoptotic proteins, translation of targets involved in cell cycle progression, angiogenesis and regulating glucose metabolism. AKT can increase surface GLUT1 expression and regulate the activation of the rate limiting enzyme phosphofructokinase-1 [55]. AKT plays a role in oocyte maturation, granulosa cell development and activation of primary follicles [56].…”

Section: Discussionmentioning

confidence: 99%

Flaxseed and its components differentially affect estrogen targets in pre-neoplastic hen ovaries

Dikshit

Gao

Small

et al. 2016

The Journal of Steroid Biochemistry and Molecular Biology

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Flaxseed has been studied for decades for its health benefits that include anti-cancer, cardioprotective, anti-diabetic, anti-inflammatory properties. The biologically active components that mediate these effects are the omega-3 fatty acids and the lignan, secoisolaricirescinol diglucoside. We have previously shown that whole flaxseed supplemented diet decreases the severity and incidence of ovarian cancer while a 15% dose of flaxseed is most protective against inflammation and estrogen-induced chemical and genotoxicity. The objective of this study was to dissect the independent effects of the two flaxseed components on estrogen signaling and metabolism. Two and half year old hens were fed either a control diet, 15% whole flaxseed diet, defatted flax meal diet or 5% flax oil diet for 3 months after which the animals were sacrificed and blood and tissues were harvested. Whole flaxseed diet caused a decrease in expression of ERα. ERα target gene expression was assessed using RT2 profiler PCR array. Some targets involved in the IGF/insulin signaling pathway (IRS1, IGFBP4, IGFBP5) were downregulated by flaxseed and its components. Flaxseed diet also downregulated AKT expression. A number of targets related to NF-κB signaling were altered by flaxseed diet including a series of targets implicated in cancer. Whole flaxseed diet also affected E2 metabolism by increasing CYP1A1 expression with a corresponding increase in the onco-protective E2 metabolite, 2-methoxyestradiol. The weak anti-estrogens, enterolactone, enterodiol and 2-methoxyestradiol, might be working synergistically to generate a protective effect on the ovaries from hens on whole flaxseed diet by altering the estrogen signaling and metabolism.

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“…Akt activation is known to regulate cell death, cell cycle progression and cell growth, as well as controlling rates of glucose uptake into the cell via the GLUT1 transporter [1]. Previous research had shown that increased levels of Akt activation directly correlate with increase rates of glucose metabolism observed in cancer cells as compared to normal cells [22]. Akt is known to further influence glycolysis by phosphorylating a number of substrates such as hexokinase 2 (HK2) [23].…”

Section: The Debate Regarding the Initiating Events Of Cancermentioning

confidence: 99%

Cancer metabolism and the Warburg effect: the role of HIF-1 and PI3K

et al. 2015

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Cancer cells have been shown to have altered metabolism when compared to normal non-malignant cells. The Warburg effect describes a phenomenon in which cancer cells preferentially metabolize glucose by glycolysis, producing lactate as an end product, despite being the presence of oxygen. The phenomenon was first described by Otto Warburg in the 1920s, and has resurfaced as a controversial theory, with both supportive and opposing arguments. The biochemical aspects of the Warburg effect outline a strong explanation for the cause of cancer cell proliferation, by providing the biological requirements for a cell to grow. Studies have shown that pathways such as phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) as well as hypoxia inducible factor-1 (HIF-1) are central regulators of glycolysis, cancer metabolism and cancer cell proliferation. Studies have shown that PI3K signaling pathways have a role in many cellular processes such as metabolism, inflammation, cell survival, motility and cancer progression. Herein, the cellular aspects of the PI3K pathway are described, as well as the influence HIF has on cancer cell metabolism. HIF-1 activation has been related to angiogenesis, erythropoiesis and modulation of key enzymes involved in aerobic glycolysis, thereby modulating key processes required for the Warburg effect. In this review we discuss the molecular aspects of the Warburg effect with a particular emphasis on the role of the HIF-1 and the PI3K pathway.

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The Role of Akt Pathway Signaling in Glucose Metabolism and Metabolic Oxidative Stress

Cited by 20 publications

References 114 publications

The insulin response integrates increased TGF-β signaling through Akt-induced enhancement of cell surface delivery of TGF-β receptors

The insulin response integrates increased TGF-β signaling through Akt-induced enhancement of cell surface delivery of TGF-β receptors

Flaxseed and its components differentially affect estrogen targets in pre-neoplastic hen ovaries

Cancer metabolism and the Warburg effect: the role of HIF-1 and PI3K

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