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.
To investigate the relationship of NKX3.1 expression and metformin efficacy in PCa.
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.
Metformin was administered before or after the induction of oxidative stress by treatment with paraquat.
Functional endpoints included analyses of histopathology, tumorigenicity, and mitochondrial function. Correlative endpoints include Kaplan-Meier curves and Cox proportional hazard regression models.
Metformin reversed the adverse consequences of NKX3.1 deficiency following oxidative stress in vivo and in vitro, as evident by reduced tumorigenicity and restored mitochondrial function. Patients with low NKX3.1 expression showed a significant clinical benefit from taking metformin.
Metformin can overcome the adverse consequences of NKX3.1 loss for PCa progression by protecting against oxidative stress and promoting normal mitochondrial function. These functional activities and clinical correlates were observed only with low NKX3.1 expression. Thus, the clinical benefit of metformin in PCa may depend on the status of NKX3.1 expression.
Prostate cancer patients with low NKX3.1 are likely to benefit most from metformin treatment to delay disease progression in a precision interception paradigm.
European urology. 2023 Aug 31 [Epub ahead of print]
Alexandros Papachristodoulou, Isabel Heidegger, Renu K Virk, Matteo Di Bernardo, Jaime Y Kim, Caroline Laplaca, Florencia Picech, Georg Schäfer, Guarionex Joel De Castro, Hanina Hibshoosh, Massimo Loda, Helmut Klocker, Mark A Rubin, Tian Zheng, Mitchell C Benson, James M McKiernan, Aditya Dutta, Cory Abate-Shen
Department of Molecular Pharmacology and Therapeutics, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA; Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA., Department of Urology, Medical University Innsbruck, Innsbruck, AT, Austria., Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA; Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA., Department of Molecular Pharmacology and Therapeutics, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA., Department of Molecular Pharmacology and Therapeutics, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA; Department of Urology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA., Department of Pathology, Medical University Innsbruck, Innsbruck, AT, Austria., Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA; Department of Urology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA., Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, NY, USA., Department of Biomedical Research, University of Bern, Bern, Switzerland., Department of Statistics, Columbia University, New York, NY, USA., Department of Urology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA., Department of Molecular Pharmacology and Therapeutics, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA. Electronic address: ., Department of Molecular Pharmacology and Therapeutics, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA; Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA; Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA; Department of Urology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA; Department of Systems Biology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA; Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA. Electronic address: .
PubMed http://www.ncbi.nlm.nih.gov/pubmed/37659962