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

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 1.3x10 5 in the control group to 9.7x10 4 and 7.1x10 4 [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. • Elevated LDH-A and GLUT-1 levels in pleural MM correlate with poor clinical outcomes. • GLUT-1 expression increased in patients after treatment with chemotherapy. • New inhibitors of GLUT-1 and LDH-A are effective against MM cells. • The the potential of targeting GLUT-1 and LDH-A for MM treatment.