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      Revving the engine: PKB/AKT as a key regulator of cellular glucose metabolism

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          Abstract

          Glucose metabolism is of critical importance for cell growth and proliferation, the disorders of which have been widely implicated in cancer progression. Glucose uptake is achieved differently by normal cells and cancer cells. Even in an aerobic environment, cancer cells tend to undergo metabolism through glycolysis rather than the oxidative phosphorylation pathway. Disordered metabolic syndrome is characterized by elevated levels of metabolites that can cause changes in the tumor microenvironment, thereby promoting tumor recurrence and metastasis. The activation of glycolysis-related proteins and transcription factors is involved in the regulation of cellular glucose metabolism. Changes in glucose metabolism activity are closely related to activation of protein kinase B (PKB/AKT). This review discusses recent findings on the regulation of glucose metabolism by AKT in tumors. Furthermore, the review summarizes the potential importance of AKT in the regulation of each process throughout glucose metabolism to provide a theoretical basis for AKT as a target for cancers.

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          The Warburg Effect: How Does it Benefit Cancer Cells?

          Cancer cells rewire their metabolism to promote growth, survival, proliferation, and long-term maintenance. The common feature of this altered metabolism is the increased glucose uptake and fermentation of glucose to lactate. This phenomenon is observed even in the presence of completely functioning mitochondria and, together, is known as the 'Warburg Effect'. The Warburg Effect has been documented for over 90 years and extensively studied over the past 10 years, with thousands of papers reporting to have established either its causes or its functions. Despite this intense interest, the function of the Warburg Effect remains unclear. Here, we analyze several proposed explanations for the function of Warburg Effect, emphasize their rationale, and discuss their controversies.
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            Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B.

            Glycogen synthase kinase-3 (GSK3) is implicated in the regulation of several physiological processes, including the control of glycogen and protein synthesis by insulin, modulation of the transcription factors AP-1 and CREB, the specification of cell fate in Drosophila and dorsoventral patterning in Xenopus embryos. GSK3 is inhibited by serine phosphorylation in response to insulin or growth factors and in vitro by either MAP kinase-activated protein (MAPKAP) kinase-1 (also known as p90rsk) or p70 ribosomal S6 kinase (p70S6k). Here we show, however, that agents which prevent the activation of both MAPKAP kinase-1 and p70S6k by insulin in vivo do not block the phosphorylation and inhibition of GSK3. Another insulin-stimulated protein kinase inactivates GSK3 under these conditions, and we demonstrate that it is the product of the proto-oncogene protein kinase B (PKB, also known as Akt/RAC). Like the inhibition of GSK3 (refs 10, 14), the activation of PKB is prevented by inhibitors of phosphatidylinositol (PI) 3-kinase.
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              Otto Warburg's contributions to current concepts of cancer metabolism.

              Otto Warburg pioneered quantitative investigations of cancer cell metabolism, as well as photosynthesis and respiration. Warburg and co-workers showed in the 1920s that, under aerobic conditions, tumour tissues metabolize approximately tenfold more glucose to lactate in a given time than normal tissues, a phenomenon known as the Warburg effect. However, this increase in aerobic glycolysis in cancer cells is often erroneously thought to occur instead of mitochondrial respiration and has been misinterpreted as evidence for damage to respiration instead of damage to the regulation of glycolysis. In fact, many cancers exhibit the Warburg effect while retaining mitochondrial respiration. We re-examine Warburg's observations in relation to the current concepts of cancer metabolism as being intimately linked to alterations of mitochondrial DNA, oncogenes and tumour suppressors, and thus readily exploitable for cancer therapy.
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                Author and article information

                Contributors
                URI : https://loop.frontiersin.org/people/2545191/overviewRole: Role:
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                Journal
                Front Physiol
                Front Physiol
                Front. Physiol.
                Frontiers in Physiology
                Frontiers Media S.A.
                1664-042X
                08 January 2024
                2023
                : 14
                : 1320964
                Affiliations
                [1] 1 General Practice Medical Center , West China Hospital , Sichuan University , Chengdu, China
                [2] 2 Department of Rehabilitation Medicine , West China Hospital , Sichuan University , Chengdu, China
                Author notes

                Edited by: Dale Tang, Albany Medical College, United States

                Reviewed by: Keith R. Laderoute, Consultant, United States

                Mithlesh Kumar Temre, National Institute on Aging (NIH), United States

                Vasudevarao Penugurti, Duke University, United States

                Article
                1320964
                10.3389/fphys.2023.1320964
                10804622
                38264327
                7e810fe2-1cdf-4cc6-822e-51683dbda46b
                Copyright © 2024 Li, Hu, Cai, Liu, Luo and Wu.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 13 October 2023
                : 12 December 2023
                Funding
                The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article. This work was supported by grants of Sichuan Provincial Department of Health Project (No. Chuangan Yan 2022-105). This article is supported by the National Clinical Key Specialty Construction Project.
                Categories
                Physiology
                Review
                Custom metadata
                Cell Physiology

                Anatomy & Physiology
                akt,glucose uptake,glucose glycolysis,cancer,tricarboxylic acid cycle
                Anatomy & Physiology
                akt, glucose uptake, glucose glycolysis, cancer, tricarboxylic acid cycle

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