Sinularin stabilizes FOXO3 protein to trigger prostate cancer cell intrinsic apoptosis

Area of Science:

• Marine Natural Products
• Cancer Biology
• Molecular Pharmacology

Background:

• Sinularin, a soft coral-derived natural product, shows anti-tumor potential against various cancers.
• The precise molecular mechanisms underlying Sinularin's anti-cancer effects remain largely unelucidated.

Purpose of the Study:

• To investigate the anti-tumor mechanisms of Sinularin in human prostate cancer cells.
• To elucidate how Sinularin induces apoptosis and identify its molecular targets.

Main Methods:

• Cell viability assays (MTT) and flow cytometry were used to assess cytotoxicity and apoptosis.
• Western blotting and quantitative real-time PCR were employed to analyze protein and gene expression.
• Mitochondrial membrane potential and protein release assays were conducted.
• Ubiquitin-proteasome pathway inhibition and kinase activity assays were performed.

Main Results:

• Sinularin significantly inhibited prostate cancer cell viability and induced apoptosis in a dose-dependent manner.
• Sinularin upregulated pro-apoptotic proteins (Bax, PUMA) and downregulated anti-apoptotic protein (Bcl-2).
• Sinularin induced mitochondrial dysfunction and activated the intrinsic apoptotic pathway.
• Sinularin stabilized FOXO3 by inhibiting AKT and ERK1/2 mediated phosphorylation and subsequent degradation via the ubiquitin-proteasome pathway.

Conclusions:

• Sinularin exerts anti-cancer effects by inducing apoptosis through the intrinsic pathway, involving PUMA and FOXO3.
• Sinularin's mechanism involves inhibiting FOXO3 degradation by suppressing AKT and ERK1/2 signaling.
• Sinularin demonstrates potential as a therapeutic agent for human prostate cancer.