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An Orthotopic Murine Model of Human Prostate Cancer Metastasis
Published on: September 18, 2013
Metformin Overcomes the Consequences of NKX3.1 Loss to Suppress Prostate Cancer Progression
Alexandros Papachristodoulou1, Isabel Heidegger2, Renu K Virk3
1Department 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.
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.
Outcome Measurements And Statistical Analysis:
Functional endpoints included analyses of histopathology, tumorigenicity, and mitochondrial function. Correlative endpoints include Kaplan-Meier curves and Cox proportional hazard regression models.
Results And Limitations:
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.
Conclusions:
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.
Patient Summary:
Prostate cancer patients with low NKX3.1 are likely to benefit most from metformin treatment to delay disease progression in a precision interception paradigm.
Insights
Metformin may benefit prostate cancer (PCa) patients by counteracting oxidative stress and improving mitochondrial function, particularly in those with low NKX3.1 expression. This suggests a potential role for metformin in precision medicine for PCa.
Area of Science:
- Oncology
- Pharmacology
- Mitochondrial Biology
Background:
- Metformin, an antidiabetic drug, exhibits anticancer properties linked to antioxidant activity.
- Its clinical efficacy in prostate cancer (PCa) remains inconclusive.
- NKX3.1, a prostate-specific gene, plays a role in mitochondrial protection against oxidative stress.
Purpose of the Study:
- To investigate the relationship between NKX3.1 expression and metformin's efficacy in prostate cancer.
- To determine if NKX3.1 status influences metformin's therapeutic benefit in PCa.
Main Methods:
- Functional studies in genetically engineered mouse models and human LNCaP cells with varying NKX3.1 levels.
- Organotypic cultures and administration of metformin before or after paraquat-induced oxidative stress.
- Correlative analyses of tissue microarrays and prostate biopsy cohorts using Kaplan-Meier curves and Cox regression.
Main Results:
- Metformin treatment reversed negative effects of NKX3.1 deficiency post-oxidative stress in vitro and in vivo.
- Tumorigenicity was reduced, and mitochondrial function was restored in NKX3.1-deficient models treated with metformin.
- Patients with low NKX3.1 expression demonstrated significant clinical benefit from metformin therapy.
Conclusions:
- Metformin can mitigate adverse effects of NKX3.1 loss in PCa progression by managing oxidative stress and mitochondrial function.
- The therapeutic benefits of metformin in PCa are specifically observed in cases of low NKX3.1 expression.
- Metformin's clinical utility in PCa may be dependent on NKX3.1 expression levels, supporting a precision interception approach.
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