Puerarin inhibits Benign prostatic hyperplasia through regulating HIF-1α-HIF-1β/ AKT1/AP-1

Hypoxia-induced cell proliferation, angiogenesis and EMT may be involved in Benign prostatic hyperplasia (BPH) development. Puerarin is an extract of traditional Chinese medicine and has anti-oxidative stress, anti-inflammation and anti-tumor activities. We proposed to explore the therapeutic effect of Puerarin on BPH development and the possible mechanism of its action. HIF-1 signaling pathway molecules in human BPH samples were assayed. Hypoxia-induced cells model of BPH cells (BPH-1) as well as BPH model in vivo were established and the effect of Puerarin on cell proliferation was measured by EDU staining and CCK8. The level of ROS, SOD was detected using commercially available kits. Formation of HIF-1α/HIF-1β Dimers and HIF-1α-HIF-1β/ AKT1/AP-1 expression was measured and located using immunofluorescence, immunohistochemistry and wester blotting. Results indicated that Puerarin could inhibit cell proliferation, angiogenesis and EMT in hypoxia-induced BPH-1 and prostate of BPH mice. Mechanistically, Puerarin significantly downregulates the HIF-1α-HIF-1β/AKT1/AP-1 signaling axis under hypoxic conditions. These therapeutic effects were substantially attenuated by either the HIF-1α agonist deferoxamine (DFO) or genetic overexpression of HIF-1α/β. Notably, HIF-1β knockdown completely abolished HIF-1α-mediated pathological progression in BPH, including cellular proliferation, angiogenesis, and EMT processes. Our results suggested that hypoxia-induced cell proliferation, angiogenesis and EMT may positively correlate with BPH development and Puerarin might suppress BPH through regulated HIF-1α- HIF-1β/AKT1/ AP-1 especially dimer of HIF-1α and HIF-1β.