.png){kind=icon}
.png){kind=icon}
Return
Post-translational modifications of triosephosphate isomerase reveal metabolic vulnerabilities in T-ALL effect of combining dichloroacetic acid and the PPI rabeprazole
.png){kind=icon}
PRE
AI
Y
D
G
G
I
S
A
G
J
F
C
L
S
DOI：10.1042/BCJ20253451.png)
.png){kind=icon}
Original request for help.png){kind=icon}
Share.png){kind=icon}
Save
Abstract
En 中文
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.
Keywords:
PROTON PUMP INHIBITORS
ACUTE LYMPHOBLASTIC-LEUKEMIA
SODIUM DICHLOROACETATE
C-JUN
METHYLGLYOXAL
APOPTOSIS
PROLIFERATION
Journal
IF:
4.3
Papers:
1.5W
Citations:
3.8W
Organization
Cited Papers