A new inhibitor of glucose-6-phosphate dehydrogenase blocks pentose phosphate pathway and suppresses malignant proliferation and metastasis in vivo

Mele, Luigi; Paino, Francesca; Papaccio, Federica; Regad, Tarik; Boocock, David J.; Stiuso, Paola; Lombardi, Angela; Liccardo, Davide; Aquino, Gabriella; Barbieri, Antônio; Arra, Claudio; Coveney, Clare; Noce, Marcella La; Papaccio, Gianpaolo; Caraglia, Michele; Tirino, Virginia; Desiderio, Vincenzo

doi:10.1038/s41419-018-0635-5

Cited by 166 publications

(131 citation statements)

References 47 publications

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“…In a previous study conducted in our laboratory, we found that G6PD overexpression promoted RCC cell proliferation and tumorigenesis through the positive feedback regulation of p-STAT3 (16). A recent study demonstrated that the blockade of G6PD by polydatin not only leads to cell cycle arrest and cell apoptosis, but also inhibits tumor cell invasion, reduces tumor size and inhibits lymph node metastasis, indicating therefore the crucial role of G6PD in tumor progression (50). Furthermore, the G6PD/hypoxia-inducing factor 1α pathway has been implicated in the nuclear factor-erythroid 2-related factor 2-mediated breast cancer migration (48).…”

Section: Discussionmentioning

confidence: 76%

G6PD facilitates clear cell renal cell carcinoma invasion by enhancing MMP2 expression through ROS‑MAPK axis pathway

et al. 2020

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Glucose-6-phosphate dehydrogenase (G6PD) is crucial rate-limiting enzyme of the pentose phosphate pathway (PPP). G6PD dysregulation has been reported in various types of human cancer, and the role of G6PD in cancer progression was demonstrated in numerous studies. A previous study from our laboratory described the prognostic significance of G6PD in clear cell renal cell carcinoma (ccRCC), and demonstrated its proliferative role through positive feedback regulation of the phosphorylated form of signal transducer and activator of transcription 3. However, the role of G6PD in ccRCC invasion remains unclear. In the present study, reverse transcription-quantitative (RT-q) PCR, western blotting, enzyme activity assay, transwell assay and immunohistochemistry analysis in cell model, xenograft mice model and human specimen studies were performed to evaluate the role of G6PD in ccRCC invasion. The results from the present study demonstrated that G6PD may promote ccRCC cell invasive ability by increasing matrix metalloproteinase 2 (MMP2) mRNA and protein expression both in vitro and in vivo. In addition, a positive correlation between G6PD and MMP2 expression was demonstrated by RT-qPCR and western blotting in twenty pairs of ccRCC tumor specimens and matched adjacent normal tissues. Furthermore, G6PD promoted reactive oxygen species (ROS) generation and activated the MAPK signaling pathway in ccRCC cells. In addition, ROS significantly promoted the MAPK signaling pathway activation, which in turn contributed to MMP2 overexpression in ccRCC cells. In conclusion, the present study demonstrated that G6PD may facilitate ccRCC cell invasive ability by enhancing MMP2 expression through ROS-MAPK axis pathway.

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Section: Discussionmentioning

confidence: 76%

G6PD facilitates clear cell renal cell carcinoma invasion by enhancing MMP2 expression through ROS‑MAPK axis pathway

et al. 2020

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“…Samples were then subjected to reduction, alkylation and overnight trypsinisation, following which they were dried down at 60°C for 4 h and stored at 80°C before resuspension in LCMS grade 5% acetonitrile in 0.1% formic acid for subsequent analysis. Analysis by mass spectrometry was performed on a SCIEX TripleTOF 6600 instrument as previously described [22]. Briefly, samples were analysed in both SWATH (Data Independent Acquisition) and IDA (Information Dependent Acquisition) modes for quantitation and spectral library generation respectively.…”

Section: Methodsmentioning

confidence: 99%

Exercise does not induce browning of WAT at thermoneutrality and induces an oxidative, myogenic signature in BAT

Aldiss

Lewis

Lupini

et al. 2019

Preprint

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Background and aimExercise training elicits diverse effects on brown (BAT) and white adipose tissue (WAT) physiology in rodents. However, these animals are typically housed below their thermoneutral zone (i.e. 28-32°C). In these conditions, BAT is chronically hyperactive and, unlike human residence, closer to thermoneutrality. Therefore, we set out to determine the effects of exercise training in obese animals at 28°C (i.e. thermoneutrality) on BAT and WAT in its basal (i.e. inactive) state.MethodsSprague-Dawley rats (n=12) were housed at thermoneutrality from 3 weeks of age and fed a high-fat diet (HFD). At 12 weeks of age half these animals were randomised to 4-weeks of exercise exercise training, i.e. swim-training (1 hour/day, 5 days per week). Metabolic assessment was undertaken during the final 48h and was followed by interscapular and perivascular BAT and inguinal (I)WAT sampling for the analysis of thermogenic genes and the proteome.ResultsExercise attenuated weight gain but did not affect fat mass or general metabolic parameters (i.e. fasting insulin and glucose). Interestingly, although BAT mass was increased, there was no change in thermogenic gene expression. Differentially regulated proteins in BAT enriched gene ontology (GO) terms including 2-oxoglutarate metabolic process, cytochrome-c activity and mitochondrial respiratory chain complex IV. This was accompanied by an upregulation of multiple proteins and GO terms involved in skeletal muscle physiology suggesting an adipocyte to myocyte switch in BAT. UCP1 mRNA was undetectable in IWAT despite an increase in classical ‘browning’ markers (i.e. PGC1a and ADRB3) with exercise. Enriched GO terms in IWAT included DNA binding and positive regulation of apoptosis. Impact analysis highlighted carbon metabolism and OXPHOS pathways were regulated by exercise in BAT whilst HIF-1 signalling and cytokine-cytokine receptor interaction were among those modified in IWAT.ConclusionExercise training reduces weight gain in obese animals at thermoneutrality and is accompanied by an oxidative, myogenic signature in BAT, rather than induction of thermogenic genes. This may represent a new, UCP1-independent pathway through which BAT regulates body weight at thermoneutrality.

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“…Samples were then subjected to reduction, alkylation and overnight trypsinisation following which they were dried down at 60°C for 4 h and stored at 80°C before resuspension in LCMS grade 5% acetonitrile in 0.1% formic acid for subsequent analysis. Analysis by mass spectrometry was carried out as previously described on a SCIEX TripleTOF 6600 instrument [12]. Briefly, samples were analysed in both SWATH (Data Independent Acquisition) and IDA (Information Dependent Acquisition) modes for quantitation and spectral library generation respectively.…”

Section: Methodsmentioning

confidence: 99%

Cold exposure drives weight gain and adiposity following chronic suppression of brown adipose tissue

Aldiss

Lewis

Lupini

et al. 2019

Preprint

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Background and aim:Rodents are commonly housed below thermoneutrality and this exposure to 'cold' (i.e. 20°C) activates thermogenic brown (BAT) and beiging of white adipose tissue. Here, we examined whether a standard housing temperature (i.e. 20°C, a reduction in temperature of ~8°C) or YM-178, a highly-selective β 3-adrenoreceptor agonist, in obese animals raised at thermoneutrality, would impact differently on classical BAT or subcutaneous inguinal (IWAT) beige depots. Methods: Eighteen weanling Sprague-Dawley rats were housed at thermoneutrality (28°C) and fed a high-fat diet. At 12 weeks, 6 animals were randomised to either standard housing temperature (20°C, n=6) or to β 3-AR agonist administration (28°C+β3, 0.75mg/kg/d, n=6) for 4 weeks. Metabolic assessment was undertaken during the final 48h, followed by interscapular, perivascular BAT and IWAT sampling for the analysis of thermogenic genes and the proteome. Results: Exposure to 20°C increased weight gain, BAT and IWAT mass. Proteomic analysis of BAT revealed novel pathways associated with cold-induced weight gain (i.e. histone deacetylation, glycosaminoglycan degradation and glycosphingolipid biosynthesis) whilst β 3adrenoreceptor agonism impacted on proteins involved in skeletal muscle contraction and cell differentiation. IWAT of cold-exposed animals exhibited an enrichment of proteins involved NAD+ binding, plus retinol and tyrosine metabolic pathways whilst β 3-AR agonism downregulated ribosomal and upregulated acute phase response proteins. Conclusion: Following diet-induced obesity at thermoneutrality, exposure to 20°C promotes subcutaneous fat deposition in order to reduce heat loss and defend body temperature. In contrast, chronic administration of β 3-AR agonist has minimal metabolic-related effects on adipose tissue.

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A new inhibitor of glucose-6-phosphate dehydrogenase blocks pentose phosphate pathway and suppresses malignant proliferation and metastasis in vivo

Cited by 166 publications

References 47 publications

G6PD facilitates clear cell renal cell carcinoma invasion by enhancing MMP2 expression through ROS‑MAPK axis pathway

G6PD facilitates clear cell renal cell carcinoma invasion by enhancing MMP2 expression through ROS‑MAPK axis pathway

Exercise does not induce browning of WAT at thermoneutrality and induces an oxidative, myogenic signature in BAT

Cold exposure drives weight gain and adiposity following chronic suppression of brown adipose tissue

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