Targeting glucose transport and the NAD pathway in tumor cells with STF-31: a re-evaluation

Kraus, Dominik; Reckenbeil, Jan; Veit, Nadine; Kuerpig, Stefan; Meisenheimer, Michael; Beier, Imke; Stark, Helmut; Winter, Jochen; Probstmeier, Rainer

doi:10.1007/s13402-018-0385-5

Cited by 55 publications

(49 citation statements)

References 28 publications

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“…Immunoblot analysis of GSC33 and GSC28 upon treatment with 1 µM CR-42-24, silenced the protein expression of GLUT1 and TUBB4 compared to untreated controls. Fasentin’s mechanism is well understood in the inhibition of GLUT1, however, its role in suppressing tumor growth has been vaguely discussed [40], but not yet within the context of diffuse gliomas, and certainly not in GBM. Immunoblot results indicate that GSC33 and GSC28 cells treated with 50 µM fasentin showed a loss of GLUT1 expression.…”

Section: Resultsmentioning

confidence: 99%

GLUT1 and TUBB4 in Glioblastoma Could be Efficacious Targets

Guda

Labak

Omar

et al. 2019

Cancers

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Glioblastoma multiforme (GBM) is the most aggressive and deadly brain tumor, portending a median 13-month survival even following gross total resection with adjuvant chemotherapy and radiotherapy. This prognosis necessitates improved therapies for the disease. A target of interest for novel chemotherapies is the Warburg Effect, which describes the tumor’s shift away from oxidative phosphorylation towards glycolysis. Here, we elucidate GLUT1 (Glucose transporter 1) and one of its associated binding partners, TUBB4 (Tubulin 4), as potentially druggable targets in GBM. Using data mining approach, we demonstrate that GLUT1 is overexpressed as a function of tumor grade in astrocytoma’s and that its overexpression is associated with poorer prognosis. Using both mass spectrometry performed on hGBM (human glioblastoma patient specimen) and in silico modeling, we show that GLUT1 interacts with TUBB4, and more accurately demonstrates GLUT1’s binding with fasentin. Proximity ligation assay (PLA) and immunoprecipitation studies confirm GLUT1 interaction with TUBB4. Treatment of GSC33 and GSC28 cells with TUBB4 inhibitor, CR-42-24, reduces the expression of GLUT1 however, TUBB4 expression is unaltered upon fasentin treatment. Using human pluripotent stem cell antibody array, we demonstrate reduced levels of Oct3/4, Nanog, Sox2, Sox17, Snail and VEGFR2 (Vascular endothelial growth factor receptor 2) upon CR-42-24 treatment. Overall, our data confirm that silencing TUBB4 or GLUT1 reduce GSC tumorsphere formation, self-renewal and proliferation in vitro. These findings suggest GLUT1 and its binding partner TUBB4 as druggable targets that warrant further investigation in GBM.

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Section: Resultsmentioning

confidence: 99%

GLUT1 and TUBB4 in Glioblastoma Could be Efficacious Targets

Guda

Labak

Omar

et al. 2019

Cancers

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“…One might well doubt the specificity of these inhibitors, especially with cytochalasin B acting as a disruptor of the cytoskeleton [31,32]. Casting this aside, however, the most important finding of this experiment was an effect of STF-31, a GLUT1-inhibitor [33,34], under hypoxia only. This indicates that SGLT1 is indeed supplemented by another transport mechanism, i.e., GLUT1, although not by GLUT2 as postulated before [10,30,35].…”

Section: Discussionmentioning

confidence: 99%

The Fast Lane of Hypoxic Adaptation: Glucose Transport Is Modulated via A HIF-Hydroxylase-AMPK-Axis in Jejunum Epithelium

Dengler

Gäbel

2019

IJMS

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The intestinal epithelium is able to adapt to varying blood flow and, thus, oxygen availability. Still, the adaptation fails under pathologic situations. A better understanding of the mechanisms underlying the epithelial adaptation to hypoxia could help to improve the therapeutic approach. We hypothesized that the short-term adaptation to hypoxia is mediated via AMP-activated protein kinase (AMPK) and that it is coupled to the long-term adaptation by a common regulation mechanism, the HIF-hydroxylase enzymes. Further, we hypothesized the transepithelial transport of glucose to be part of this short-term adaptation. We conducted Ussing chamber studies using isolated lagomorph jejunum epithelium and cell culture experiments with CaCo-2 cells. The epithelia and cells were incubated under 100% and 21% O2, respectively, with the panhydroxylase inhibitor dimethyloxalylglycine (DMOG) or under 1% O2. We showed an activation of AMPK under hypoxia and after incubation with DMOG by Western blot. This could be related to functional effects like an impairment of Na+-coupled glucose transport. Inhibitor studies revealed a recruitment of glucose transporter 1 under hypoxia, but not after incubation with DMOG. Summing up, we showed an influence of hydroxylase enzymes on AMPK activity and similarities between hypoxia and the effects of hydroxylase inhibition on functional changes.

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“…STF-31 (45) (Kraus et al, 2018), an intrinsically dual acting drug with an inhibitory activity on NAMPT and GLUT1, and KPT-9274 (or ATG-019) (46) can be considered the archetypical examples of this novel class of compounds. The latter is a dual inhibitor of p21-activated kinase (PAK4) and NAMPT with potent cytotoxic activity on B-ALL cells and with the ability to function in vivo in a xenograft murine model.…”

Section: Dual Inhibitorsmentioning

confidence: 99%

Recent Advances in NAMPT Inhibitors: A Novel Immunotherapic Strategy

et al. 2020

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Nicotinamide adenine dinucleotide (NAD) is a cofactor of many enzymatic reactions as well as being a substrate for a number of NAD-consuming enzymes (e.g., PARPS, sirtuins, etc). NAD can be synthesized de novo starting from tryptophan, nicotinamide, nicotinic acid, or nicotinamide riboside from the diet. On the other hand, the nicotinamide that is liberated by NAD-consuming enzymes can be salvaged to reform NAD. In this former instance, nicotinamide phosphoribosyltransferase (NAMPT) is the bottleneck enzyme. In the many cells in which the salvage pathway is predominant, NAMPT, therefore, represents an important controller of intracellular NAD concentrations, and as a consequence of energy metabolism. It is, therefore, not surprising that NAMPT is over expressed by tumoral cells, which take advantage from this to sustain growth rate and tumor progression. This has led to the initiation of numerous medicinal chemistry programs to develop NAMPT inhibitors in the context of oncology. More recently, however, it has been shown that NAMPT inhibitors do not solely target the tumor but also have an effect on the immune system. To add complexity, this enzyme can also be secreted by cells, and in the extracellular space it acts as a cytokine mainly through the activation of Toll like Receptor 4 (TLR4), although it has not been clarified yet if this is the only receptor responsible for its actions. While specific small molecules have been developed only against the intracellular form of NAMPT, growing evidences sustain the possibility to target the extracellular form. In this contribution, the most recent evidences on the medicinal chemistry of NAMPT will be reviewed, together with the key elements that sustain the hypothesis of NAMPT targeting and the drawbacks so far encountered.

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Targeting glucose transport and the NAD pathway in tumor cells with STF-31: a re-evaluation

Cited by 55 publications

References 28 publications

GLUT1 and TUBB4 in Glioblastoma Could be Efficacious Targets

GLUT1 and TUBB4 in Glioblastoma Could be Efficacious Targets

The Fast Lane of Hypoxic Adaptation: Glucose Transport Is Modulated via A HIF-Hydroxylase-AMPK-Axis in Jejunum Epithelium

Recent Advances in NAMPT Inhibitors: A Novel Immunotherapic Strategy

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