Heteronemin, a marine sesterterpenoid-type
natural product, possesses diverse bioactivities, especially antitumor effect. Accumulating evidence shows that
heteronemin may act as a potent
anticancer agent in clinical
therapy. To fully understand the antitumor mechanism of
heteronemin, we further explored the precise molecular targets in
prostate cancer cells. Initially,
heteronemin exhibited potent cytotoxic effect against LNcap and PC3
prostate cancer cells with IC50 1.4 and 2.7 μM after 24 h, respectively. In the xenograft animal model, the
tumor size was significantly suppressed to about 51.9% in the
heteronemin-treated group in comparison with the control group with no significant difference in the mice
body weights. In addition, the results of a cell-free system assay indicated that
heteronemin could act as
topoisomerase II (
topo II) catalytic inhibitor through the elimination of essential enzymatic activity of
topoisomerase IIα expression. We found that the use of
heteronemin-triggered apoptosis by 20.1⁻68.3%, caused disruption of mitochondrial membrane potential (
MMP) by 66.9⁻99.1% and promoted
calcium release by 1.8-, 2.0-, and 2.1-fold compared with the control group in a dose-dependent manner, as demonstrated by
annexin-V/PI,
rhodamine 123 and
Fluo-3 staining assays, respectively. Moreover, our findings indicated that the pretreatment of LNcap cells with an inhibitor of
protein tyrosine phosphatase (PTPi) diminished growth inhibition, oxidative and Endoplasmic Reticulum (ER) stress, as well as activation of Chop/Hsp70 induced by
heteronemin, suggesting PTP activation plays a crucial rule in the cytotoxic activity of
heteronemin. Using molecular docking analysis,
heteronemin exhibited more binding affinity to the N-terminal
ATP-binding pocket of Hsp90
protein than
17-AAG, a standard Hsp90 inhibitor. Finally,
heteronemin promoted autophagy and apoptosis through the inhibition of Hsp 90 and
topo II as well as PTP activation in
prostate cancer cells. Taken together, these multiple targets present
heteronemin as an interesting candidate for its future development as an antiprostatic agent.