THE ANDROGEN RECEPTOR (AR) EXPRESSION DETERMINES THE ANDROGENIC CONTROL OF HYPOXIA-INDUCED STROMAL CELL PROLIFERATION IN BENIGN PROSTATIC HYPERPLASIA

NAHUEL PEINETTI; AMADO ALFREDO QUINTAR; CUELLO RUBIO MARIANA MICAELA; CRISTINA ALICIA MALDONADO; LOPEZ SEOANE, MANUEL

Buenos Aires- DIGITAL

Congreso; SAIC SAI SAFIS 2020; 2020

Sociedad Argentina de Investigación Clínica

Benign prostatic hyperplasia (BPH) is characterized by an epithelial and stromal proliferative process, with testosterone being classically considered the most important factor involved in its pathophysiology. However, BPH occurs in older men, when androgen levels are usually dropped. Accumulated evidence indicates that BPH is associated with a hypoxic microenvironment which contributes to cell proliferation. We therefore investigated the effect of hypoxia on BPH stromal cell proliferation and the role of testosterone on this hypoxic context. Prostatic stromal cells, surgically harvested from patients with BPH (n=12, obtained under informed consent and approved by the Comité Institucional de Ética de Investigación en Salud of Sanatorio Allende), were isolated, cultured, and stimulated with CoCl2 (200 µM), a stabilizer of hypoxia-inducible factor-1 (HIF-1) that mimics hypoxia, alone or in combination with testosterone at physiological doses (0.1 µM) for 24h.As expected, CoCl2 induced the expression of HIF-1α, as determined by western blot, which was correlated to a 2-to-4-fold increase in cell proliferation (by ki67 and BrdU incorporation) in all cultures (p˂0.01 vs. vehicle). Testosterone decreased both HIF-1α expression (p˂0.01 vs. CoCl2) and cell proliferation (p˂0.01 vs. CoCl2) induced by CoCl2 in 8 out 12 patient-derived cell cultures. In the remaining 4 cases, the testosterone treatment resulted in the upregulation of HIF-1α and cell proliferation, which was associated with a low expression of the androgen receptor (AR), by western blot, when compared to the previous 8 cell cultures. Then, our aim was to increase the basal levels of AR in those cells by pre-treating them with testosterone for 8h. Afterwards, the cells were subjected to hypoxia, with testosterone being able to repress both CoCl2-induced HIF-1α and cell proliferation and thus, changing its behavior.Our results indicate that a hypoxic context increases cell proliferation in BPH stromal cells and androgens play a dual role in hypoxic microenvironments which depend on the expression levels of the AR.