Papachristodoulou Alexandros, Heidegger Isabel, Virk Renu K, Di Bernardo Matteo, Kim Jaime Y, Laplaca Caroline, Picech Florencia, Schäfer Georg, De Castro Guarionex Joel, Hibshoosh Hanina, Loda Massimo, Klocker Helmut, Rubin Mark A, Zheng Tian, Benson Mitchell C, McKiernan James M, Dutta Aditya, Abate-Shen Cory
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.
Eur Urol. 2024 Apr;85(4):361-372. doi: 10.1016/j.eururo.2023.07.016. Epub 2023 Aug 31.
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.
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.
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.
抗糖尿病药物二甲双胍具有与其抗氧化活性相关的已知抗癌作用；然而，其对前列腺癌（PCa）的临床益处迄今尚无定论。在此，我们研究二甲双胍在PCa中的疗效是否与NKX3.1的表达状态有关，NKX3.1是一种前列腺特异性同源框基因，在线粒体中发挥作用以保护前列腺免受异常氧化应激。
研究NKX3.1表达与二甲双胍在PCa中的疗效之间的关系。
设计、场所和参与者：在基因工程小鼠模型和人LNCaP细胞以及NKX3.1水平正常或降低/缺失的器官型培养物中进行体内和体外功能研究。使用两个独立的前列腺癌根治术回顾性组织微阵列队列和一个主动监测患者的前列腺活检回顾性队列进行相关性研究。
在用百草枯处理诱导氧化应激之前或之后给予二甲双胍。
功能终点包括组织病理学、肿瘤发生能力和线粒体功能分析。相关终点包括Kaplan-Meier曲线和Cox比例风险回归模型。
二甲双胍在体内和体外逆转了氧化应激后NKX3.1缺乏的不良后果，表现为肿瘤发生能力降低和线粒体功能恢复。NKX3.1表达低的患者服用二甲双胍显示出显著的临床益处。
二甲双胍可通过抵御氧化应激和促进正常线粒体功能来克服NKX3.1缺失对PCa进展的不良后果。仅在NKX3.1低表达时观察到这些功能活性和临床相关性。因此，二甲双胍在PCa中的临床益处可能取决于NKX3.1的表达状态。
NKX3.1低表达的前列腺癌患者可能最受益于二甲双胍治疗，以在精准拦截模式下延迟疾病进展。
