Sestrin2 ameliorates age-related spontaneous benign prostatic hyperplasia via activation of AMPK/mTOR dependent autophagy.

Abstract

Benign prostatic hyperplasia (BPH), characterized as a chronic disease with unregulated enlargement of prostatic gland, is commonly observed in elderly men leading to lower urinary tract dysfunction. Sestrin2 plays a role in the maintenance of cellular homeostasis and protects organisms from various stimuli. The exact role of Sestrin2 in the etiology of BPH, a common age-related disease, remains unknown. Here, we explored the regulatory function of Sestrin2 in modulating autophagy and its therapeutic role in spontaneous BPH. In vivo study, the 3-month-old (3 M) and 24-month-old (24 M) mice were used, and the 24 M mice were additionally administered recombinant Sestrin2 protein (rp-Sestrin2) for consecutive 14 days. In vitro, BPH-1 cells were transfected with an empty or Sestrin2 overexpression vector. Sestrin2 expression in mice prostate was gradually declined with age. Administration of rp-Sestrin2 to these mice suppressed prostatic hyperplasia, restored the balance between proliferation and apoptosis, and reduced prostatic fibrosis. Moreover, rp-Sestrin2 treatment enhanced autophagy by activating AMP-activated protein kinase (AMPK)/ mammalian target of rapamycin (mTOR) signaling pathway, as evidenced by increased autophagosome and autolysosome formation, along with a decrease in degradation marker such as p62. Our findings were further supported by in vitro studies, where Sestrin2 overexpression induced autophagy via AMPK/mTOR signaling pathway. These results suggest that Sestrin2 plays a critical role in attenuating spontaneous BPH by regulating autophagy through AMPK/mTOR signaling pathway. This study provides novel insights into the therapeutic potential of Sestrin2 in age-related spontaneous BPH.