In vitro and in silico studies of holothurin A on androgen receptor in prostate cancer

The androgen receptor (AR) plays a crucial role in the growth of prostate cancer, and has long been considered the cancer's primary strategic therapeutic target. However, despite the early susceptibility, patients receiving hormonal therapy targeting AR are likely to develops resistance to the treatment and progresses to the castration-resistant stage as a consequence of the mutation at the ligand binding pocket of AR. Interestingly, the surface pocket of the AR called binding function 3 (BF3) has been reported as a great benefit for treating a recurrent tumor. Herein, we investigate the potential of using a marine triterpenoid saponin, holothurin A, on targeting AR expression of prostate cancer using in vitro and in silico studies. Holothurin A reduced the PSA expression, leading to the growth inhibition of androgen sensitive prostate cancer cell line through a downregulation of AR activity. The molecular docking study demonstrated that holothurin A could bind strongly in the BF3 pocket by energetically favorable hydrogen acceptor and hydrophobic with a calculated binding affinity of -13.90 kcal/mol. Molecular dynamics simulations provided the additional evidence that holothurin A can form a stable complex with the BF3 pocket through the hydrophobic interactions with VAL676, ILE680, and ALA721. As a consequence, holothurin A modulates the activation function-2 (AF2) site of the AR through repositioning of the residues in the AF2 pocket. Targeting alternatives sites on the surface of AR via holothurin A will provide a potential candidate for future prostate cancer treatment.