Glutamine synthesis pathway promotes the survival and recurrence of dormant tumor cells in prostate cancer.

Cancer cell dormancy presents a major obstacle to curative therapy, particularly in metastatic prostate cancer. Although the initial efficacy of hormonal therapy is satisfying, tumors will inevitably develop resistance. Dormant tumor cells may act as the initial source for the tumor recurrence, but the underlying mechanism remains largely unknown. Here we report that the glutamine synthesis pathway is required for cellular dormancy under androgen-deprived conditions. The key enzyme, glutamine synthetase (encoded by glutamate-ammonia ligase, GLUL), is upregulated during hormonal therapy, which leads to overabundant glutamine as a nutrient and an energy storage for tumor recurrence. The negative modulation of androgen receptor (AR) on GLUL enables activation of glutamine anabolism when AR is inhibited. Pharmacologically inhibiting GS's activity along with hormonal therapy results in cell apoptosis instead of dormancy, which significantly delays the progression of tumors into advanced PCa. In summary, we provide a novel perspective of how hormonal therapy eventually fails and highlight a combination treatment strategy to overcome therapeutic resistance of current hormonal therapy.