Post-translational modifications of triosephosphate isomerase reveal metabolic vulnerabilities in T-ALL: effect of combining dichloroacetic acid and the PPI rabeprazole
Por:
Martínez-Pérez Y., De la Mora-De la Mora I., Hernández-Alcántara G., López-Herrera G., García-Torres I., Gómez-Manzo S., Olaya-Vargas A., León-Avila G., Hernández-Hernandez J.M., González-Rubio F., Flores-Braulio C.Y., Flores-López L.A., Enríquez-Flores S.
Publicada:
1 ene 2026
Resumen:
Acute lymphoblastic leukemia, particularly the T-cell subtype, remains associated with poor outcomes in relapsed and adult patients, highlighting the need for novel therapeutic strategies. Metabolic reprogramming, especially glycolytic dependence, represents a promising target. Triosephosphate isomerase (TPI), a key glycolytic enzyme, undergoes cancer-associated post-translational modifications (PTMs), including deamidation and phosphorylation. Here, we evaluated the potential of proton pump inhibitors (PPIs), particularly rabeprazole (Rbz), to selectively target PTM-bearing TPI isoforms in Jurkat cell model. Recombinant TPI variants engineered to mimic PTMs exhibited increased reactivity toward thiol-modifying agents and higher predicted binding affinities for PPI compared with wild-type TPI. Consistent with these properties, biochemical assays demonstrated preferential inhibition of the deamidation- and phosphorylation-mimicking proteins, with Rbz significantly reducing their enzymatic activity. Native gel electrophoresis of Jurkat cells protein extracts revealed drug-induced accumulation of acidic TPI isoforms, whereas normal T lymphocytes predominantly retained unmodified TPI. Rbz selectively impaired intracellular TPI activity and viability in Jurkat cells, effects enhanced by dichloroacetate (DCA) co-treatment. This inhibition correlated with marked accumulation of methylglyoxal and advanced glycation end products. Finally, combined DCA–Rbz treatment induced extensive apoptotic death in Jurkat cells while sparing normal lymphocytes. These findings identify PTM-bearing TPI isoforms as selective metabolic vulnerabilities in Jurkat cells and support the potential repurposing of thiol-modifying agents, particularly, Rbz, as targeted antileukemic strategies. © 2026 Portland Press Ltd. All rights reserved.
Filiaciones:
Tecnológico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, Mexico City, 14380, Mexico
Laboratorio de Biomoléculas y Salud Infantil, Instituto Nacional de Pediatría, Mexico City, 04530, Mexico
Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Apartado Postal 70-159, Mexico City, 04510, Mexico
Laboratorio de Inmunodeficiencias, Instituto Nacional de Pediatría, México City, 04530, Mexico
Laboratorio de Bioquímica Genética, Instituto Nacional de Pediatría, Mexico City, 04530, Mexico
Trasplante de Células Madre y Terapia Celular, Instituto Nacional de Pediatría, Mexico City, 04530, Mexico
Departamento de Zoología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Carpio y Plan de Ayala S/N, Casco de Santo Tomás, Mexico City, 11340, Mexico
Departamento de Biología Celular. CINVESTAV, Av. IPN 2508. Col., San Pedro Zacatenco, Mexico City, 07360, Mexico
Licenciatura en Biología, Facultad de Ciencias, Universidad Nacional Autónoma de México, Mexico City, 04510, Mexico
Laboratorio de Biomoléculas y Salud Infantil, SECIHTI-Instituto Nacional de Pediatría, Mexico City, 04530, Mexico
hybrid, All Open Access; Hybrid Gold Open Access
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