A glutaminase isoform switch drives therapeutic resistance and disease progression of prostate cancer

Significance We report that androgen receptor (AR) promotes glutaminase 1 (GLS1) expression and glutamine utilization to support the survival of prostate cancer (PCa) cells. Hormonal therapy inhibits AR and decreases GLS1 expression and glutamine utilization to achieve therapeutic effect. Our results suggest that eventually the tumor cells switch GLS1 expression from the AR-dependent KGA isoform to the androgen-independent and enzymatically more potent GAC isoform, which increases glutamine utilization and can contribute to the development of castration-resistant PCa. Our work has discovered a previously unknown AR function, a metabolic mechanism of hormonal therapy and an important therapeutic target more specific than AR. Targeting GLS1 may achieve similar therapeutic efficacy but without the side effects resulting from inhibiting AR’s other important physiologic functions.