Matrine induces aggressive prostate cancer cell death via inhibition of PPARα activity: insights from transcriptomics, molecular docking, and functional studies.
Abstract
Background
Prostate cancer remains a significant global health burden with limited treatment options for advanced stages. Matrine, a natural alkaloid from Sophora flavescens, has demonstrated anti-cancer potential. This study aimed to investigate its efficacy against aggressive prostate cancer cell death and elucidate the underlying molecular mechanism.
Methods
The anti-proliferative effects of matrine were assessed in multiple prostate cancer cell lines (LNCaP, C4-2, PC3, Du145) using CCK-8, EdU, and colony formation assays. A subcutaneous xenograft model using PC3 cells in nude mice evaluated in vivo efficacy. Transcriptomic sequencing of matrine-treated PC3 cells identified altered pathways. Molecular docking analyzed the interaction between matrine and peroxisome proliferator-activated receptor α (PPARα). PPAR activity was measured via luciferase reporter assays, and subcellular localization was examined by immunofluorescence. Data were analyzed using Student's t-test or Mann-Whitney U test.
Results
Matrine dose-dependently inhibited cell viability, proliferation, and colony formation, with enhanced effects on aggressive, androgen-independent PC3 and Du145 cells. In vivo, matrine (100 mg/kg) suppressed tumor growth without significant toxicity. Transcriptomics revealed significant downregulation of lipid metabolism pathways, particularly the PPAR signaling pathway. Functional studies showed matrine suppressed general PPAR activity. Subsequent experiments identified PPARα as the primary target: matrine exhibited high binding affinity to PPARα in silico, inhibited its nuclear translocation and transcriptional activity, and its anti-proliferative effects were effectively reversed by a PPARα-specific agonist.
Conclusions
This study demonstrates that matrine effectively suppresses aggressive prostate cancer cell death both in vitro and in vivo. The mechanism involves the inhibition of PPARα activity, leading to the disruption of associated lipid metabolism pathways. These findings highlight matrine as a natural PPARα inhibitor and provide a novel therapeutic rationale for targeting PPARα in prostate cancer treatment.