(-)-Oleuropein as a Novel Metastatic Castration-Resistant Prostate Cancer Progression and Recurrence Suppressor via...

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Prostate cancer (PC) is a common malignancy with high recurrence rates, especially castration-resistant PC (CRPC).
• Existing therapies like androgen deprivation face inevitable resistance, leading to high mortality.
• The Mediterranean diet, rich in olive phenolics, shows potential in cancer prevention.

Purpose of the Study:

• To investigate the effects of (-)-oleuropein (OLE), an olive leaf phenolic glucoside, on mCRPC progression and recurrence.
• To explore the molecular mechanisms underlying OLE's action, focusing on PCSK9 and LDLR pathways.

Main Methods:

• In vitro studies on human PC cell lines assessing OLE's effects on viability, migration, and clonogenicity.
• In silico modeling to analyze OLE's interaction with PCSK9 and its protein-protein interaction (PPI) with LDLR.
• In vivo studies using a nude mouse xenograft model to evaluate OLE's efficacy against mCRPC.
• RNA sequencing to identify molecular changes in OLE-treated tumors.

Main Results:

• OLE downregulated proprotein convertase subtilisin/klexin type 9 (PCSK9) and normalized the low-density lipoprotein receptor (LDLR) in PC cells.
• In silico analysis confirmed OLE's potential to interfere with the PCSK9-LDLR PPI.
• OLE demonstrated modest suppressive effects on PC cell viability, migration, and clonogenicity in vitro.
• OLE significantly suppressed mCRPC progression and recurrence in vivo and downregulated PCSK9, PCSK1, and PCSK2 expression in tumors.

Conclusions:

• (-)-Oleuropein shows promise as a novel therapeutic lead for managing mCRPC.
• OLE's mechanism involves targeting PCSK9 expression and its PPI with LDLR, offering a new strategy for controlling cancer progression and preventing recurrence.