Dynamic evaluation of the glycolytic determinants LDH-A and GLUT-1 enhances prognostic significance and their inhibition affects the growth of mesothelioma spheroids

Our plain-English summary of Dynamic evaluation of the glycolytic determinants LDH-A and GLUT-1 enhances prognostic significance and their inhibition affects the growth of mesothelioma spheroids, by M.A. Franczak, F. Borea, V. Donati, et al (Molecular Metabolism, 2026).

The study

• Authors: M.A. Franczak, F. Borea, V. Donati, M. Aliprandi, A. Avan, V. Doldi, G. Bononi, K.Y. Tam, C. Granchi, R.T. Smolenski, P.A. Zucali, F. Minutolo, G.J. Peters, E. Giovannetti
• Journal: Molecular Metabolism
• Published: 2026;107:102356
• Cited by: 1 article, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Energy metabolism plays a crucial role in determining the aggressiveness of cancer. In this study, we assessed the impact of drug-induced modulation on the expression and prognostic significance of crucial factors involved in glycolytic metabolism: lactate dehydrogenase A (LDH-A) and glucose transporter type 1 (GLUT-1). In patient samples diagnosed with pleural Malignant Mesothelioma (MM), expression levels of LDH-A and GLUT-1 were studied both at baseline and after platinum-based-chemotherapy. High GLUT-1 and LDH-A levels were associated with shorter survival, and chemotherapy increased GLUT-1 expression, further correlating with poor prognosis. Utilizing LDH-A (NHI-2) and GLUT-1 (PGL14) inhibitors, we examined their effects on migration and apoptosis in immortalized (H2052, H2452) and primary (STO, MESO-II) MM cells. PGL14 and NHI-2 decreased migration, increased reactive oxygen species (ROS) and apoptosis rates. Inhibitors, both single and in combination, disintegrated the MM spheroids, while the bioluminescence from spheroid-forming cells decreased from 1.3 × 105 in the control group to 9.7 × 104 and 7.1 × 104 [RLU/s] after NHI-2 and PGL14/NHI-2 treatment, respectively. Overexpression and chemotherapy-induced modulation of LDH-A and GLUT-1 correlated with poor MM prognosis. Combined inhibition of these two metabolic determinants impeded MM cell migration, stimulated ROS production and apoptosis, and affected spheroids' growth, offering promise for new treatment development.

Copyright © 2026 The Author(s). Published by Elsevier GmbH.. All rights reserved.

In plain English

This study used tumor tissue from pleural malignant mesothelioma (MM) patients and laboratory-grown pleural and peritoneal MM cells. It did not examine asbestos exposure. The authors stained tumors from 57 patients for two sugar-metabolism proteins, LDH-A and GLUT-1, and compared survival. Median overall survival was 13.1 months (95% CI, 9.9 to 16.3) with high LDH-A versus 20.9 months (95% CI, 15.0 to 26.8) with low LDH-A (P = 0.014). With high versus low GLUT-1 it was 13.6 months (95% CI, 10.3 to 16.8) versus 20.9 months (95% CI, 14.0 to 27.8; P = 0.004). Twenty-four patients had tissue from before and after platinum-pemetrexed chemotherapy. GLUT-1 rose in 11 of them and LDH-A changed in only 3. Patients whose GLUT-1 rose had worse prognosis, the authors reported (p = 0.001). In the cells, two experimental inhibitors, NHI-2 (against LDH-A) and PGL14 (against GLUT-1), reduced migration. Used together, they increased cell death. They also disrupted three-dimensional cell clusters called spheroids. The authors noted small patient numbers and few non-epithelioid tumors. They concluded that targeting LDH-A and GLUT-1 shows promise for new treatments.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study combining immunohistochemical staining of patient tumor tissue with survival analysis, plus cell-culture experiments (cell lines and 3-dimensional spheroids)
• Who was studied: Tumor samples from 57 pleural MM patients: 33 on tissue microarrays (before treatment) and 24 with tissue before and after chemotherapy, from Humanitas Research Hospital, Rozzano, Milan, Italy (2004 to 2020). Also pleural MM cell lines H2052 and H2452 and primary peritoneal MM cells MESO-II and STO.
• Exposure: No asbestos exposure was studied. Exposures were platinum-based chemotherapy with pemetrexed (patients), cisplatin, pemetrexed and gemcitabine (cells), and the experimental inhibitors NHI-2 (LDH-A) and PGL14 (GLUT-1) (cells).
• Main results:
  • Of the 57 pleural MM cases, 31 (54%) had high LDH-A and 25 (44%) had high GLUT-1 expression
  • Patients with high LDH-A had median overall survival of 13.1 months (95% CI, 9.9 to 16.3) versus 20.9 months (95% CI, 15.0 to 26.8) with low LDH-A; P = 0.014
  • Patients with high GLUT-1 had median overall survival of 13.6 months (95% CI, 10.3 to 16.8; P = 0.004) versus 20.9 months (95% CI, 14.0 to 27.8) with low GLUT-1
  • The 25 of 57 patients with both high LDH-A and high GLUT-1 had shorter overall survival than the other patients (14.2 vs. 28.5 months; P = 0.002)
  • Among 24 patients with tissue before and after chemotherapy, LDH-A changed in only 3 and GLUT-1 increased in 11 (46%)
  • Grouping patients by change in GLUT-1 after chemotherapy (no change vs. increase) showed a significant survival difference (p = 0.001)
  • The authors described patients whose GLUT-1 increased after treatment as having a worse prognosis
  • In H2052 pleural MM cells, GLUT-1 and LDH-A gene expression was significantly higher after cisplatin, gemcitabine, pemetrexed and their combination
  • Both inhibitors significantly decreased migration of H2452 cells, most of all PGL14; a similar pattern was seen in H2052 cells and in peritoneal primary cells STO and MESO-II
  • Combined treatment increased apoptosis (cell death) in pleural (H2052) and peritoneal (MESO-II) cells at the IC50 and twice the IC50 concentrations
  • PGL14 produced 3 times higher reactive oxygen species (ROS) production in H2052 and MESO-II cells
  • In STO spheroids, GLUT-1 inhibition and combination treatment caused visible disintegration. Bioluminescence from spheroid-forming cells fell from 1.3 × 10^5 (control) to 9.7 × 10^4 after NHI-2 and 7.1 × 10^4 after PGL14 plus NHI-2 (RLU/s).
• The authors' conclusion: The authors concluded that targeting LDH-A and GLUT-1 shows potential as a strategy for developing new treatments for MM
• Limitations the authors state:
  • Statistical analyses were done on small patient cohorts
  • Too few non-epithelioid tumors to draw conclusions about differences by histological subtype
  • LDH-A changed after chemotherapy in only 3 patients, so it could not be analysed statistically; the authors call for a larger cohort
  • Not all cell lines could be used in every experiment; spheroids could not be made from MESO-II cells

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Lactate Dehydrogenase (LDH), Chemotherapy, Prognosis, Apoptosis, Reactive Oxygen Species (ROS).

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