# TXNIP upregulation controls metabolism and cell cycle during androgen deprivation therapy in prostate cancer

## TL;DR

TXNIP controls metabolism and cell cycle in prostate cancer during androgen deprivation therapy, and its levels predict treatment response and progression to advanced disease.

## Contribution

TXNIP is identified as a novel regulator of therapeutic response to androgen deprivation therapy in prostate cancer.

## Key findings

- TXNIP suppresses glycolysis by sequestering GLUT1 and promotes glutaminolysis in prostate cancer.
- Low TXNIP levels correlate with poor response to androgen deprivation therapy and progression to CRPC.
- Nuclear TXNIP induces cell cycle arrest by upregulating p27kip1, which is lost in CRPC.

## Abstract

Thioredoxin-Interacting Protein (TXNIP) is an arrestin at the crossroad of redox and glycolytic metabolisms. Prostate cancer (PCa) exhibits a unique metabolic profile due to the glycolytic nature of healthy prostate tissue. We hypothesize that TXNIP plays a pivotal role in the progression of PCa to castration-resistant prostate cancer (CRPC), an incurable stage of the disease characterized by profound metabolic reprogramming and independence from androgens. Only a subset of patients progresses to CRPC, and current stratification tools lack robust biomarkers. TXNIP expression is directly suppressed by androgens and diminishes during tumor initiation and progression, as demonstrated in both human samples and a prostate adenocarcinoma mouse model (TRAMP). TXNIP regulates glucose metabolism by sequestering the glucose transporter GLUT1 away from the membrane, shifting metabolism from glycolysis to glutaminolysis. Nuclear-localized TXNIP induces cell cycle arrest through the upregulation of p27kip1 which is downregulated together with TXNIP in CRPC. The response to androgen deprivation therapy (ADT) strongly depends on TXNIP expression. In the murine model, TXNIP levels were significantly higher in ADT responders compared to non-responders. Furthermore, TRAMP-Txnip−/− prostate tumors exhibited a poorer response to ADT, with increased Ki67 and enhanced viability. In clinical samples, all patients on relapse showed low levels of TXNIP and progressed to CRPC. Our findings identify TXNIP as a critical regulator of cell cycle and glucose metabolism in PCa and emphasize for the first time its essential role in mediating therapeutic responses to ADT.