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

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Abstract

Background

Targeting glucose metabolism is a promising way to interfere with tumor cell proliferation and survival. However, controversy exists about the specificity of some glucose metabolism targeting anticancer drugs. Especially the potency of STF-31 has been debated. Here, we aimed to assess the impact of the glucose transporter (GLUT) inhibitors fasentin and WZB117, and the nicotinamide phosphoribosyltransferase (NAMPT) inhibitors GMX1778 and STF-31 on tumor cell proliferation and survival, as well as on glucose uptake.

Methods

Tumor-derived A172 (glioblastoma), BHY (oral squamous cell carcinoma), HeLa (cervix adenocarcinoma), HN (head neck cancer), HT-29 (colon carcinoma) and MG-63 (osteosarcoma) cells were treated with fasentin, WZB117, GMX1778 and STF-31. Proliferation rates and cell viabilities were assessed using XTT, crystal violet and LDH assays. mRNA and protein expression of GLUT1 and NAPRT were assessed using qPCR and Western blotting, respectively. The effects of inhibiting compounds on glucose uptake were measured using [18F]-fluoro-deoxyglucose uptake experiments.

Results

Stimulation of tumor-derived cells with the different inhibitors tested revealed a complex pattern, whereby proliferation inhibiting and survival reducing concentrations varied in [18F]-fluoro-deoxyglucose uptake experiments more than one order of magnitude among the different cells tested. We found that the effects of GMX1778 and STF-31 could be partially abolished by (i) nicotinic acid (NA) only in nicotinic acid phosphoribosyltransferase (NAPRT) expressing cells and (ii) nicotinamide mononucleotide (NMN) in all cells tested, supporting the classification of these compounds as NAMPT inhibitors. In short-time [18F]-fluoro-deoxyglucose uptake experiments the application of WZB-117 was found to lead to an almost complete uptake inhibition in all cells tested, whereas the effect of fasentin was found to be cell type dependent with a maximum value of ~35% in A172, BHY, HeLa and HT-29 cells. We also found that STF-31 inhibited glucose uptake in all cells tested in a range of 25–50%. These data support the classification of STF-31 as a GLUT inhibitor.

Conclusions

Our data reveal a dual mode of action of STF-31, serving either as a NAMPT or as a GLUT inhibitor, whereby the latter seems to be apparent only at higher STF-31 concentrations. The molecular basis of such a dual function and its appearance in compounds previously designated as NAMPT-specific inhibitors requires further investigation.

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Fig. 1: Glycolysis and mammalian NAD + metabolic pathways.
Fig. 2: Metabolic perturbation by GLUT inhibitors in tumor cells after short-time culture.
Fig. 3: Rescue effects in NAMPT or GLUT inhibitor treated tumor cells after long-time culture in the absence or presence of NA or NMN.
Fig. 4: Glucose uptake inhibition in NAMPT or GLUT inhibitor treated tumor cells.

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Author notes

  1. Jochen Winter and Rainer Probstmeier contributed equally to this work.

Authors and Affiliations

  1. Department of Prosthodontics, Preclinical Education, and Material Sciences, University of Bonn, Bonn, Germany

    Dominik Kraus, Jan Reckenbeil, Imke Beier & Helmut Stark

  2. Neuro- and Tumor Cell Biology Group, Department of Nuclear Medicine, University of Bonn, Bonn, Germany

    Nadine Veit & Rainer Probstmeier

  3. Department of Nuclear Medicine, University of Bonn, Bonn, Germany

    Stefan Kuerpig & Michael Meisenheimer

  4. Oral Cell Biology Group, Department of Periodontology, Operative and Preventive Dentistry, University of Bonn, Bonn, Germany

    Jochen Winter

  5. Neuro- and Tumor Cell Biology Group, Department of Nuclear Medicine, University Hospital of Bonn, Sigmund-Freud-Str. 25, D-53127, Bonn, Germany

    Rainer Probstmeier

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  1. Dominik Kraus
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Correspondence to Rainer Probstmeier.

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Kraus, D., Reckenbeil, J., Veit, N. et al. Targeting glucose transport and the NAD pathway in tumor cells with STF-31: a re-evaluation. Cell Oncol. 41, 485–494 (2018). https://doi.org/10.1007/s13402-018-0385-5

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