Demethylmycemycin A, a dibenzoxazepinone from the marine-derived Dactylosporangium sp. OK1079, with prostate cancer suppressive effects via targeting BRK-FAK-STAT3 axis

Abstract

Breast tumor kinase (Brk) is an intracellular kinase that initiates a downstream oncogenic signaling through phosphorylation of focal adhesion kinase (FAK) and signal transducer and activator of transcription 3 (STAT3). Demethylmycemycin A (DA) was isolated from a sponge-derived Dactylosporangium sp. OK1079. Though known as a microbial dibenzoxazepinone, its biological activity has never been investigated. Previous studies on the marine triterpene sipholenol A identified its perhydrobenzoxepine system as the key pharmacophore that mediated its Brk binding. The bioisosteric similarity of DA to the sipholenol A perhydrobenzoxepine motivated a molecular docking simulation of DA for potential Brk binding. The antiproliferative effect of DA was investigated against diverse prostate cancer (PC) cell lines including LNCaP (castration/hormone-sensitive primary adenocarcinoma), PC3, and 22Rv1 (castration-resistant), in addition to the androgen-independent DU145 cells. LNCaP cells were the most sensitive to the effects of DA, followed by PC3, showing IC₅₀ values of 7.6 and 9.8 μM, respectively. DA treatments significantly reduced the migration and clonogenicity of the LNCaP cells. Western blot analysis indicated the ability of DA to reduce the expression levels of activated Brk, FAK and STAT3 in a dose-dependent manner in both cell lines. DA also decreased the expression levels of the total FAK but didn't affect the total level of Brk while the expression level of total STAT3 was only suppressed in LNCaP cells. These results highlight the PC proliferation and migration suppressive effects of DA through targeting Brk-FAK-STAT3 axis. DA is a potential prototype hit that can be developed particularly for Brk-expressing PC control.