The androgen receptor (ar) expression determines the androgenic control of hypoxia- induced stromal cell proliferation in benign prostatic hyperplasia

PEINETTI NAHUEL; QUINTAR AMADO A; CUELLO RUBIO MARIANA; MALDONADO CRISTINA A; LÓPEZ SEOANE MANUEL

Evento virtual

Congreso; LXV Reunión Anual de la Sociedad Argentina de Investigación Clínica (SAIC); 2020

Sociedad Argentina de Investigación Clínica

Benign prostatic hyperplasia (BPH) is characterized by an epithelialand stromal proliferative process, with testosterone being classicallyconsidered the most important factor involved in its pathophysiology.However, BPH occurs in older men, when androgen levelsare usually dropped. Accumulated evidence indicates that BPH isassociated with a hypoxic microenvironment which contributes tocell proliferation. We therefore investigated the effect of hypoxia onBPH stromal cell proliferation and the role of testosterone on thishypoxic context. Prostatic stromal cells, surgically harvested frompatients with BPH (n=12, obtained under informed consent andapproved by the Comité Institucional de Ética de Investigación enSalud of Sanatorio Allende), were isolated, cultured, and stimulatedwith CoCl2 (200 μM), a stabilizer of hypoxia-inducible factor-1 (HIF-1) that mimics hypoxia, alone or in combination with testosterone atphysiological doses (0.1 μM) for 24h.As expected, CoCl2 induced the expression of HIF-1α, as determinedby western blot, which was correlated to a 2-to-4-fold increasein cell proliferation (by ki67 and BrdU incorporation) in allcultures (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 theupregulation of HIF-1α and cell proliferation, which was associatedwith a low expression of the androgen receptor (AR), by westernblot, when compared to the previous 8 cell cultures. Then, our aimwas to increase the basal levels of AR in those cells by pre-treatingthem with testosterone for 8h. Afterwards, the cells were subjectedto hypoxia, with testosterone being able to repress both CoCl2-inducedHIF-1α and cell proliferation and thus, changing its behavior.Our results indicate that a hypoxic context increases cell proliferationin BPH stromal cells and androgens play a dual role in hypoxicmicroenvironments which depend on the expression levels of theAR.