Ganoderic Acid A Suppresses Androgenindependent Cell Growth via the AKT/GSK-3β/β-catenin Signaling Pathway

Abstract

Objectives: The primary aim of this study is to investigate the specific effects and mechanisms of ganoderic acid A (GAA) on castration-resistant prostate cancer (CRPC).Materials and Methods: We successfully established an androgen-independent prostate cancer cell line (LNCaP-AI). The LNCaP-AI cells demonstrated accelerated growth, elevated levels of androgen receptor and prostate-specific antigen (PSA), and resistance to the drug enzalutamide. Then, we administered LNCaP-AI cells with GAA or a control and determined the cell growth rate. Next, LNCaP-AI cells with and without GAA treatment were subjected to RNA-seq for mRNA sequencing. The genes were subjected to a Kyoto Encyclopedia of Genes and Genomes analysis. We also checked the expression levels of the targeted genes. Finally, normal LNCaP or LNCaP-AI cells were subcutaneously injected into nude mice to further confirm the effect of GAA.Results: Experiments showed that GAA effectively suppressed the growth rate, PSA secretion, migration, and invasion of LNCaP-AI cells. The results of a subsequent RNA-seq analysis identified the PI3K/AKT pathway as the key signaling pathway influenced by GAA. Notably, AKT and GSK-3β phosphorylation was decreased, and β-catenin protein levels were also lowered, as a result of GAA treatment. Moreover, we observed decreased activity in crucial genes, including c-Myc, Cyclin D1, and MMP-2, which play integral roles in CRPC development. Furthermore, GAA inhibited the tumorigenesis of LNCaP-AI cells in nude mice in vivo.Conclusion: GAA effectively suppresses the growth of androgen-independent cells by inhibiting the AKT/GSK-3β/β-catenin signaling pathway. These findings demonstrate the potential of GAA as a therapeutic candidate for CRPC.

Keywords: Castration-resistant prostate cancer; ganoderic acid A; β-catenin; LNCaP-AI; androgen deprivation therapy