Homeostatic effects of testosterone in the hypoxic microenvironment of Benign Prostatic Hyperplasia
Benign prostatic hyperplasia (BPH) is characterized by an increase in stromal cell proliferation of the transitional zone of the prostate, with evidence suggesting that this is associated with a hypoxic microenvironment, which would induce proliferation through the transcription factor HIF-1. In pro...
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| Autores principales: | , , , , |
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| Formato: | Artículo revista |
| Lenguaje: | Español |
| Publicado: |
Universidad Nacional Córdoba. Facultad de Ciencias Médicas. Secretaria de Ciencia y Tecnología
2019
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| Materias: | |
| Acceso en línea: | https://revistas.unc.edu.ar/index.php/med/article/view/25655 |
| Aporte de: |
| Sumario: | Benign prostatic hyperplasia (BPH) is characterized by an increase in stromal cell proliferation of the transitional zone of the prostate, with evidence suggesting that this is associated with a hypoxic microenvironment, which would induce proliferation through the transcription factor HIF-1. In prostate cancer, HIF-1 is highly regulated by testosterone but little is known about the role of androgens on HIF-1 in BPH. Our objective was therefore to evaluate the effect of hypoxia on stromal cell proliferation and phenotype and the regulatory role of testosterone.
Prostatic stromal cells harvested from patients with BPH (n=10, approved by the Bioethics Committee of Sanatorio Allende) were cultured and stimulated with CoCl2 (200 µM), a stabilizer of HIF-1 that mimics hypoxia, alone or in combination with testosterone (T) at high (10 µM), physiological (0.1 µM), and low (1nM) concentrations for 24 hours. The expression and nuclear translocation of HIF-1 were measured by western blot and immunofluorescence. Cell proliferation was assessed by immunocytochemistry of Ki67 and BrDu incorporation, whereas the cellular phenotype was confirmed by transmission electron microscopy (TEM) and western blot of cytoskeletal markers for stromal cells.
CoCl2 upregulated the expression and nuclear translocation of HIF-1, associated with increased cell proliferation (3.10 ± 0.17% vs. CoCl2: 10.77 ± 4.51%, p <0.05). The presence of testosterone at low and physiological doses reduced these parameters, indicating a protective role of the androgen in hypoxic conditions (CoCl2 + T [0.1 µM]: 5.59 ± 2.25%). In control cells, TEM analysis showed signs of activation such as cellular edema, dilation of the endoplasmic reticulum, with multiple foci of contractile myofibrils, compatible with a myofibroblastic profile. Hypoxia increased these signs, with frequent myocontractile fibrils, while the presence of testosterone maintained a cell phenotype similar to the controls.
Our results suggest that a hypoxic microenvironment promotes a HIF-1-mediated hyperproliferative cell phenotype in BPH, with testosterone modulating the cellular response to hypoxia. Therefore, HIF-1 inhibition would be likely a molecular mechanism involved in the homeostatic effects of testosterone in this pathology. |
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