Two ubiquitin ligases, APC/C-Cdh1 and SKP1-CUL1-F (SCF)-β-TrCP, sequentially regulate glycolysis during the cell cycle

Tudzarova, Slavica; Colombo, Sergio; Stoeber, Kai; Carcamo, Saul; Williams, Gareth; Moncada, Salvador

doi:10.1073/pnas.1102247108

Cited by 119 publications

(116 citation statements)

References 19 publications

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“…Although there is substantial evidence to support increased glycolysis in tumor versus normal tissue, recently there have been reports indicating that glycolysis is closely linked with the cell cycle and that increased glucose metabolism is a consequence of growth signaling within a cell (normal or tumor) and not necessarily as a result of "rewiring" of a cancer cell (32). Nonetheless, increased glucose metabolism seems to be a hallmark of cancer, which is likely due to their uncontrolled and constant movement through the cell cycle as well as other factors associated with oncogenic transformation (30,33).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Akt Potentiates 2-DG–Induced Apoptosis via Downregulation of UPR in Acute Lymphoblastic Leukemia

DeSalvo

Kuznetsov

et al. 2012

Molecular Cancer Research

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The ability to pair the regulation of metabolism and cellular energetics with oncogenes and tumor suppressor genes provides cancer cells with a growth and survival advantage over normal cells. We investigated the mechanism of cell death induced by 2-deoxy-D-glucose (2-DG), a sugar analog with dual activity of inhibiting glycolysis and Nlinked glycosylation, in acute lymphoblastic leukemia (ALL). We found that, unlike most other cancer phenotypes in which 2-DG only inhibits cell proliferation under normoxic conditions, ALL lymphoblasts undergo apoptosis. Bp-ALL cell lines and primary cells exhibited sensitivity to 2-DG, whereas T-ALL cells were relatively resistant, revealing phenotypic differences within ALL subtypes. Cotreatment with D-mannose, a sugar essential for N-linked glycosylation, rescues 2-DG-treated ALL cells, indicating that inhibition of N-linked glycosylation and induction of ER stress and the unfolded protein response (UPR) is the predominant mechanism of 2-DG's cytotoxicity in ALL. 2-DG-treated ALL cells exhibit upregulation of P-AMPK, P-Akt, and induction of ER stress/UPR markers (IRE1a, GRP78, P-eIF2a, and CHOP), which correlate with PARP cleavage and apoptosis. In addition, we find that pharmacologic and genetic Akt inhibition upregulates P-AMPK, downregulates UPR, and sensitizes ALL cells to remarkably low doses of 2-DG (0.5 mmol/L), inducing 85% cell death and overcoming the relative resistance of T-ALL. In contrast, AMPK knockdown rescues ALL cells by upregulating the prosurvival UPR signaling. Therefore, 2-DG induces ALL cell death under normoxia by inducing ER stress, and AKT and AMPK, traditionally thought to operate predominantly on the glycolytic pathway, differentially regulate UPR activity to determine cell death or survival. Mol Cancer Res; 10(7); 969-78. Ó2012 AACR. IntroductionAcute lymphoblastic leukemia (ALL) is the most common malignancy in children and adolescents and is a leading cause of cancer-related deaths in these patients (1). Current clinical practices have had only minimal impact on cure rates for patients with resistant phenotypes or after relapse (2, 3). A number of ALL phenotypes exhibit mutations that lead to inactivation or constitutive activation of oncogenic pathways such as LKB1, PTEN, PI3K/Akt and RAS, which have been linked to the regulation of energy metabolism in general and glucose metabolism in particular (4-6). T-ALL is known to have a high rate of PTEN mutations that lead to constitutive activation of Akt (7). Our laboratory has previously shown that the master energy regulator AMPK has significant

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Section: Discussionmentioning

confidence: 99%

Inhibition of Akt Potentiates 2-DG–Induced Apoptosis via Downregulation of UPR in Acute Lymphoblastic Leukemia

DeSalvo

Kuznetsov

et al. 2012

Molecular Cancer Research

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“…The feature, which has been termed Warburg Effect (1), is observed not only in cancer cells but also in most of proliferating cells (2). An increase in lactate production was found in G 1 phase in HeLa cells (3). Inhibition of glycolysis halted cell-cycle progression in G 1 phase in HeLa cells (4).…”

Section: Introductionmentioning

confidence: 98%

Energy Management by Enhanced Glycolysis in G1-phase in Human Colon Cancer Cells In Vitro and In Vivo

Bao

Mukai

Hishiki

et al. 2013

Molecular Cancer Research

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Activation of aerobic glycolysis in cancer cells is well known as the Warburg effect, although its relation to cellcycle progression remains unknown. In this study, human colon cancer cells were labeled with a cell-cycle phasedependent fluorescent marker Fucci to distinguish cells in G 1 -phase and those in S þ G 2 /M phases. Fucci-labeled cells served as splenic xenograft transplants in super-immunodeficient NOG mice and exhibited multiple metastases in the livers, frozen sections of which were analyzed by semiquantitative microscopic imaging mass spectrometry. Results showed that cells in G 1 -phase exhibited higher concentrations of ATP, NADH, and UDP-N-acetylglucosamine than those in S and G 2 -M phases, suggesting accelerated glycolysis in G 1 -phase cells in vivo. Quantitative determination of metabolites in cells synchronized in S, G 2 -M, and G 1 phases suggested that efflux of lactate was elevated significantly in G 1 -phase. By contrast, ATP production in G 2 -M was highly dependent on mitochondrial respiration, whereas cells in S-phase mostly exhibited an intermediary energy metabolism between G 1 and G 2 -M phases. Isogenic cells carrying a p53-null mutation appeared more active in glycolysis throughout the cell cycle than wild-type cells. Thus, as the cell cycle progressed from G 2 -M to G 1 phases, the dependency of energy production on glycolysis was increased while the mitochondrial energy production was reciprocally decreased.Implications: These results shed light on distinct features of the phase-specific phenotypes of metabolic systems in cancer cells. Mol Cancer Res; 11(9); 973-85. Ó2013 AACR.

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“…PFKFB1 and PFKFB4 are specific isoenzymes of liver/kidney and testis tissues, respectively (1,25). In HeLa cells, predominant expression of PFKFB2 and PFKFB3 has been reported (22,26,27). To analyze whether the increase in Fru-2,6-P 2 concentrations caused by amino acids correlated with an increase in 6-phosphofructo-2-kinase (PFK-2) activity, we measured the activity of this enzyme.…”

Section: The Increase In Fru-26-p 2 Concentration Induced By Aminomentioning

confidence: 99%

Akt-dependent Activation of the Heart 6-Phosphofructo-2-kinase/Fructose-2,6-bisphosphatase (PFKFB2) Isoenzyme by Amino Acids

Novellasdemunt

Tato

Navarro-Sabaté

et al. 2013

Journal of Biological Chemistry

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Two ubiquitin ligases, APC/C-Cdh1 and SKP1-CUL1-F (SCF)-β-TrCP, sequentially regulate glycolysis during the cell cycle

Cited by 119 publications

References 19 publications

Inhibition of Akt Potentiates 2-DG–Induced Apoptosis via Downregulation of UPR in Acute Lymphoblastic Leukemia

Inhibition of Akt Potentiates 2-DG–Induced Apoptosis via Downregulation of UPR in Acute Lymphoblastic Leukemia

Energy Management by Enhanced Glycolysis in G1-phase in Human Colon Cancer Cells In Vitro and In Vivo

Akt-dependent Activation of the Heart 6-Phosphofructo-2-kinase/Fructose-2,6-bisphosphatase (PFKFB2) Isoenzyme by Amino Acids

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