Matairesinol Targets Lipid Metabolism Reprogramming in AR-Independent Prostate Cancer Cells.

objectiveMetabolic reprogramming, especially lipid reprogramming, is critical in cancer progression, including prostate cancer (PCa). Androgen deprivation therapy (ADT) is commonly used to slow down tumor spread and Lipid metabolism has been linked to its resistance in PCa. This study examines the therapeutic potential of Matairesinol (MA), a plant-derived lignan, in targeting lipid reprogramming in PCa cells.

methodsPC-3 cells were treated with different doses of MA and its effect was studied on cell growth and induction of apoptosis by trypan blue dye exclusion and JC-1 dye assays, respectively. The altered expression of de novo fatty acid, cholesterol biosynthesis and other associated genes were evaluated by qPCR. Changes in intracellular lipid accumulation were assessed by Nile red staining. The bioinformatics approach was used to identify the main targets of MA using DrugBank, PubChem, and BindingDB databases, and molecular docking was performed with Autodock 4.2 to predict the binding of MA.

resultsMA significantly impaired PCa cell growth and mitochondrial membrane potential, inducing apoptosis. MA modulated mRNA expression of fatty acid and cholesterol biosynthesis, lipid transport, and lipolysis-related genes, and reduced lipid accumulation. Bioinformatics analysis with DrugBank, PubChem, and BindingDB revealed the main targets of MA; and molecular docking with AutoDock 4.2 predicted MA binding and identified SHBG and DHRS4L2 as potential targets. In vitro validation confirmed that MA significantly reduced mRNA levels of SHBG and DHRS4L2 in PC-3 cell line.

conclusionBy targeting lipid metabolism, MA holds promising potential as a therapeutic agent for PCa, especially in ADT-resistant and Metastatic Castration Resistant Prostate Cancer (mCRPC) cases.