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      Oncogenic kinases and perturbations in protein synthesis machinery and energetics in neoplasia

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          Abstract

          Notwithstanding that metabolic perturbations and dysregulated protein synthesis are salient features of cancer, the mechanism underlying coordination of cellular energy balance with mRNA translation (which is the most energy consuming process in the cell) is poorly understood. In this review, we focus on recently emerging insights in the molecular underpinnings of the cross-talk between oncogenic kinases, translational apparatus and cellular energy metabolism. In particular, we focus on the central signaling nodes that regulate these processes (e.g. the mechanistic/mammalian target of rapamycin MTOR) and the potential implications of these findings on improving the anti-neoplastic efficacy of oncogenic kinase inhibitors.

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          Most cited references158

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          On the origin of cancer cells.

          O WARBURG (1956)
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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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              Lactate Metabolism in Human Lung Tumors

              Cancer cells consume glucose and secrete lactate in culture. It is unknown whether lactate contributes to energy metabolism in living tumors. We previously reported that human non-small cell lung cancers (NSCLC) oxidize glucose in the tricarboxylic acid (TCA) cycle. Here we show that lactate is also a TCA cycle carbon source for NSCLC. In human NSCLC, evidence of lactate utilization was most apparent in tumors with high 18 fluorodeoxyglucose uptake and aggressive oncological behavior. Infusing human NSCLC patients with 13 C-lactate revealed extensive labeling of TCA cycle metabolites. In mice, deleting monocarboxylate transporter-1 (MCT1) from tumor cells eliminated lactate-dependent metabolite labeling, confirming tumor-cell autonomous lactate uptake. Strikingly, directly comparing lactate and glucose metabolism in vivo indicated that lactate's contribution to the TCA cycle predominates. The data indicate that tumors, including bona fide human NSCLC, can use lactate as a fuel in vivo. Human non-small cell lung cancer preferentially utilizes lactate over glucose to fuel TCA cycle and sustain tumor metabolism in vivo.

                Author and article information

                Journal
                J Mol Endocrinol
                J. Mol. Endocrinol
                JME
                Journal of Molecular Endocrinology
                Bioscientifica Ltd (Bristol )
                0952-5041
                1479-6813
                February 2019
                01 August 2018
                : 62
                : 2
                : R83-R103
                Affiliations
                [1 ]Lady Davis Institute , SMBD JGH, McGill University, Montreal, Quebec, Canada
                [2 ]Department of Experimental Medicine , Montreal, Quebec, Canada
                [3 ]Gerald Bronfman Department of Oncology , Montreal, Quebec, Canada
                [4 ]Biochemistry Department , McGill University, Montreal, Quebec, Canada
                Author notes
                Correspondence should be addressed to L Hulea: laura.hulea@ 123456mail.mcgill.ca
                Article
                JME-18-0058
                10.1530/JME-18-0058
                6347283
                30072418
                219f1f36-dcd9-447f-8d12-83777d530629
                © 2018 The authors

                This work is licensed under a Creative Commons Attribution 4.0 Unported License.

                History
                : 19 July 2018
                : 01 August 2018
                Categories
                Review

                Endocrinology & Diabetes
                protein synthesis,metabolism,cancer,mtor,oncogenic kinases
                Endocrinology & Diabetes
                protein synthesis, metabolism, cancer, mtor, oncogenic kinases

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