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Review
. 2015;50(3):242-55.
doi: 10.3109/10409238.2015.1031879. Epub 2015 Apr 21.

Intersections between mitochondrial sirtuin signaling and tumor cell metabolism

Affiliations
Review

Intersections between mitochondrial sirtuin signaling and tumor cell metabolism

Karina N Gonzalez Herrera et al. Crit Rev Biochem Mol Biol. 2015.

Abstract

Cancer cells use glucose and glutamine to facilitate cell growth and proliferation, a process coined "metabolic reprograming" - an emerging hallmark of cancer. Inside the cell, these nutrients synergize to produce metabolic building blocks, such as nucleic acids, lipids and proteins, as well as energy (ATP), glutathione and reducing equivalents (NADPH), required for survival, growth and proliferation. Intense research aimed at understanding the underlying cause of the metabolic rewiring has revealed that established oncogenes and tumor suppressors involved in signaling alter cellular metabolism to contribute to the transition from a normal quiescent cell to a rapidly proliferating cancer cell VSports手机版. Likewise, bona fide metabolic sensors are emerging as regulators of tumorigenesis. This review will focus on one such family of sensors, sirtuins, which utilize NAD(+) as a cofactor to catalyze deacetylation, deacylation and ADP-ribosylation of their protein substrates. In this review, we will enumerate how cancer cell metabolism is different from a normal quiescent cell and highlight the emerging role of mitochondrial sirtuin signaling in the regulation of tumor metabolism. .

Keywords: Antioxidants; Warburg effect; glutamine metabolism; metabolic reprograming; signaling pathways. V体育安卓版.

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Figures

Figure 1
Figure 1
Alterations in glucose and glutamine metabolism contribute to tumor growth and proliferation. Rewiring of glucose and glutamine metabolism contribute to synthesis of macromolecules, antioxidants and reducing equivalents. Major enzymes involved in each pathway are highlighted above, and expression or activity of these enzymes tends to be altered in tumor cells to contribute to metabolic reprograming, as described in the text. NEAA, non-essential amino acids; HK, hexokinase; GFAT, glutamine fructose-6-phosphate amidotransferase; PHGDH, phosphoglycerate dehydrogenase; SHMT, serine hydroxymethyltransferase; PK, pyruvate kinase; PDH, pyruvate dehydrogenase; GCL, glutamate-cysteine ligase; GS, glutathione synthase; ME, malic enzyme; ACL, ATP citrate lyase; LDHA, lactate dehydrogenase; GLS, glutaminase; GDH, glutamate dehydrogenase; AST, aspartate aminotransferase; ALT, alanine aminotransferase; GLUT1, glucose transporter type 1; ASCT2, sodium-dependent neutral amino acid transporter type 2; SN2, system N transporter 2; MCT4, monocarboxylate transporter type 4; xCT, cystine/glutamate transporter. (see colour version of this figure at www.informahealthcare.com/bmg).
Figure 2
Figure 2
Oncogenic signaling pathways and tumor suppressors mediate metabolic reprograming in cancer to increase tumor growth and proliferation. Signaling cascades, such as Ras, PI3K and mTORC1, regulate metabolism and overexpression or mutations in components of these pathways contribute to altered metabolism in cancer. Additionally, signaling cascades stabilize transcription factors, such as HIF1 and c-Myc, which control metabolic gene expression to increase glycolysis or glutaminolysis. Mitochondrial sirtuins, SIRT3 and SIRT4, repress aberrant metabolism in cancer. SIRT3 represses reactive oxygen species (ROS) by deacetylating direct targets, such as manganese superoxide dismutase (SOD2) and isocitrate dehydrogenase (IDH2), to destabilize HIF1 and repress the Warburg effect. SIRT4 ADP-ribosylates glutamate dehydrogenase (GDH), and thus, represses glutaminolysis. (see colour version of this figure at www.informahealthcare.com/bmg).

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