Nutritional Limitation Sensitizes Mammalian Cells to GSK-3β Inhibitors and Leads to Growth Impairment

Candia, Paola de; Minopoli, Giuseppina; Verga, Viola; Gargiulo, Anna; Vanoni, Marco; Alberghina, Lilia

doi:10.1016/j.ajpath.2010.12.047

Cited by 10 publications

(10 citation statements)

References 32 publications

(39 reference statements)

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“…23,24,44 RAS-transformed cells show a high glycolytic rate, decreased oxidative flux through the TCA cycle, reduction of mitochondrial complex I activity and increased utilization of glutamine for anabolic synthesis. 27,35,[44][45][46] Here, we have confirmed the dominant aerobic glycolytic phenotype, the reduced oxygen consumption and the defect in complex I activity of H-RAS transformed cells. Glycolysis is strictly required for sustaining the ATP levels and the robust proliferation of RAS-transformed cells.…”

Section: Discussionsupporting

confidence: 59%

Transformation by different oncogenes relies on specific metabolic adaptations

et al. 2016

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Metabolic adaptations are emerging as common traits of cancer cells and tumor progression. In vitro transformation of NIH 3T3 cells allows the analysis of the metabolic changes triggered by a single oncogene. In this work, we have compared the metabolic changes induced by H-RAS and by the nuclear resident mutant of histone deacetylase 4 (HDAC4). RAS-transformed cells exhibit a dominant aerobic glycolytic phenotype characterized by up-regulation of glycolytic enzymes, reduced oxygen consumption and a defect in complex I activity. In this model of transformation, glycolysis is strictly required for sustaining the ATP levels and the robust cellular proliferation. By contrast, in HDAC4/TM transformed cells, glycolysis is only modestly up-regulated, lactate secretion is not augmented and, instead, mitochondrial oxygen consumption is increased. Our results demonstrate that cellular transformation can be accomplished through different metabolic adaptations and HDAC4/TM cells can represent a useful model to investigate oncogene-driven metabolic changes besides the Warburg effect.

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Section: Discussionsupporting

confidence: 59%

Transformation by different oncogenes relies on specific metabolic adaptations

et al. 2016

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“…A transformation-dependent cell kill was observed via glucose limitation in K-rastransformed NIH3T3 cells (de Candia et al 2011). GSK-3b activities in these cells were compared during high versus low glucose availability (de Candia et al 2011).…”

Section: Mutual Interactions With Ampk Activation and Gsk-3b Inhibitionmentioning

confidence: 99%

Section: Mutual Interactions With Ampk Activation and Gsk-3b Inhibitionmentioning

confidence: 99%

“…GSK-3b activities in these cells were compared during high versus low glucose availability (de Candia et al 2011). Glucose depletion blocked GSK-3b through posttranslational mechanisms, and this inhibition was lesser in normal cells (de Candia et al 2011). Additional blockage of GSK-3b with lithium, combined with glucose starvation, led to a specific induction of AMPK and significant reduction of proliferation in transformed but not normal cells.…”

Section: Mutual Interactions With Ampk Activation and Gsk-3b Inhibitionmentioning

confidence: 99%

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A Metabolic Inhibitory Cocktail for Grave Cancers: Metformin, Pioglitazone and Lithium Combination in Treatment of Pancreatic Cancer and Glioblastoma Multiforme

Elmacı

Altinöz²

2016

Biochem Genet

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Pancreatic cancer (PC) and glioblastoma multiforme (GBM) are among the human cancers with worst prognosis which require an urgent need for efficient therapies. Here, we propose to apply to treat both malignancies with a triple combination of drugs, which are already in use for different indications. Recent studies demonstrated a considerable link between risk of PC and diabetes. In experimental models, anti-diabetogenic agents suppress growth of PC, including metformin (M), pioglitazone (P) and lithium (L). L is used in psychiatric practice, yet also bears anti-diabetic potential and selectively inhibits glycogen synthase kinase-3 beta (GSK-3β). M, a biguanide class anti-diabetic agent shows anticancer activity via activating AMP-activated protein kinase (AMPK). Glitazones bind to PPAR-γ and inhibit NF-κB, triggering cell proliferation, apoptosis resistance and synthesis of inflammatory cytokines in cancer cells. Inhibition of inflammatory cytokines could simultaneously decrease tumor growth and alleviate cancer cachexia, having a major role in PC mortality. Furthermore, mutual synergistic interactions exist between PPAR-γ and GSK-3β, between AMPK and GSK-3β and between AMPK and PPAR-γ. In GBM, M blocks angiogenesis and migration in experimental models. Very noteworthy, among GBM patients with type 2 diabetes, usage of M significantly correlates with better survival while reverse is true for sulfonylureas. In experimental models, P synergies with ligands of RAR, RXR and statins in reducing growth of GBM. Further, usage of P was found to be lesser in anaplastic astrocytoma and GBM patients, indicating a protective effect of P against high-grade gliomas. L is accumulated in GBM cells faster and higher than in neuroblastoma cells, and its levels further increase with chronic exposure. Recent studies revealed anti-invasive potential of L in GBM cell lines. Here, we propose that a triple-agent regime including drugs already in clinical usage may provide a metabolic adjuvant therapy for PC and GBM.

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“…6). Lithium reportedly inhibits the glycogen synthase kinase-3β, a serine/threonine kinase that controls cell cycle progression; lithium treatment causes G2/M arrest while preserving cell viability (Mao et al, 2001), and inhibits growth in NIH3T3 cells (Candia et al, 2011).…”

Section: Effect Of Residual Libr On the Secondary Structure Of Sf Filmsmentioning

confidence: 99%

Effect of Residual Lithium Ions on the Structure and Cytotoxicity of Silk Fibroin Film

Yang¹,

Kwak²,

Lee³

2013

International Journal of Industrial Entomology

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Dialysis is the rate-limiting step in the preparation of aqueous silk fibroin (SF) solution. However, the traditional practice of dialyzing SF solution for at least 48 h to remove LiBr is not based on empirical evidence. The aim of the present study was to systematically measure LiBr content in SF solutions dialyzed for varying lengths of time and assess the potential toxicity of residual lithium ions in cells. Complete removal of lithium ions was not achieved even after 72 h of dialysis, with a residual lithium ion content in the solution of 22.85 mg/l. SF films prepared from solutions dialyzed for 8 and 24 h had predominantly random coil or b-sheet structures, respectively. The residual lithium had little cytotoxicity in NIH3T3 fibroblast cells, but viability was compromised in cells grown on SF film prepared from solution dialyzed for 24 h. IntroductionSilk fibroin (SF) is a biocompatible material with various biomedical applications, for instance as a drug delivery vehicle or a scaffold in tissue engineering (Ki et al., 2009). SF also possesses the advantages of tunable mechanical properties and biodegradability; for instance, a more flexible SF film can be made by increasing water content (Hu et al., 2008), while the time required for SF degradation can be altered by controlling molecular weight distribution (Cao et al., 2009) Hu et al., 2012). It is also possible to prepare a transparent film from SF (Lawrence et al., 2009), making it a highly versatile substance for optoelectronics (Capelli et al., 2011).and crystallinity (SF is initially prepared as an aqueous solution before being manufactured into various forms including fiber, film, sponges, nano-and microparticles, and hydrogel. The multi-step process includes the removal of sericin by degumming using sodium carbonate solution with or without surfactant. The SF is then dissolved in 9.3 M LiBr solution, which is accelerated by higher temperatures: complete dissolution requires more than 12 h at room temperature, but at 60°C or higher the time is reduced to less than an hour. The removal of excess LiBr by dialysis is the rate-limiting step during the preparation of SF solution, with a recommended time of more than 48 h (Rockwood et al., 2011

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Nutritional Limitation Sensitizes Mammalian Cells to GSK-3β Inhibitors and Leads to Growth Impairment

Cited by 10 publications

References 32 publications

Transformation by different oncogenes relies on specific metabolic adaptations

Transformation by different oncogenes relies on specific metabolic adaptations

A Metabolic Inhibitory Cocktail for Grave Cancers: Metformin, Pioglitazone and Lithium Combination in Treatment of Pancreatic Cancer and Glioblastoma Multiforme

Effect of Residual Lithium Ions on the Structure and Cytotoxicity of Silk Fibroin Film

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