Metformin Overcomes the Consequences of NKX3.1 Loss to Suppress Prostate Cancer Progression

Background: The antidiabetic drug metformin has known anticancer effects related to its antioxidant activity; however, its clinical benefit for prostate cancer (PCa) has thus far been inconclusive. Here, we investigate whether the efficacy of metformin in PCa is related to the expression status of NKX3.1 , a prostate -specific homeobox gene that functions in mitochondria to protect the prostate from aberrant oxidative stress. Objective: To investigate the relationship of NKX3.1 expression and metformin efficacy in PCa. Design, setting, and participants: Functional studies were performed in vivo and in vitro in genetically engineered mouse models and human LNCaP cells, and organotypic cultures having normal or reduced/absent levels of NKX3.1. Correlative studies were performed using two independent retrospective tissue microarray cohorts of radical prostatectomies and a retrospective cohort of prostate biopsies from patients on active surveillance. Intervention: Metformin was administered before or after the induction of oxidative stress by treatment with paraquat.