c-Myc-driven glycolysis via TXNIP suppression is dependent on glutaminase-MondoA axis in prostate cancer

Area of Science:

• * Molecular Biology
• * Cancer Metabolism
• * Oncology

Background:

• * Oncogenic c-Myc drives metabolic reprogramming, creating dependencies on glucose and glutamine.
• * Thioredoxin-interacting protein (TXNIP) is a key negative regulator of glucose uptake.
• * Understanding nutrient utilization offers therapeutic targets for cancer.

Purpose of the Study:

• * To elucidate the mechanism by which c-Myc suppresses TXNIP in prostate cancer cells.
• * To investigate the role of glutaminolysis and glutaminase (GLS1) in this process.
• * To explore the therapeutic potential of targeting the c-Myc-GLS1-TXNIP axis.

Main Methods:

• * Utilized prostate cancer cell lines.
• * Employed glutamine depletion, GLS1 inhibition (siRNA, CB-839), and ectopic TXNIP expression.
• * Analyzed TXNIP promoter activity with a mutant E-Box region.
• * Assessed c-Myc-induced glucose uptake and glycolytic gene expression.

Main Results:

• * c-Myc suppresses TXNIP predominantly through GLS1-mediated glutaminolysis activation.
• * Glutamine depletion or GLS1 inhibition restored c-Myc-repressed TXNIP expression.
• * c-Myc represses TXNIP by blocking MondoA activity, as shown by mutant E-Box assays.
• * Ectopic TXNIP expression reduced c-Myc-driven glucose uptake and glycolytic gene expression.
• * The c-Myc/TXNIP relationship correlates with patient outcomes in prostate adenocarcinomas (PCAs).

Conclusions:

• * TXNIP is a critical mediator of c-Myc-driven aerobic glycolysis.
• * The c-Myc-GLS1-TXNIP pathway represents a potential therapeutic strategy in prostate cancer.
• * Targeting this axis may impact tumor aggressiveness and patient outcomes.