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.Communicated by Ramaswamy H. Sarma.