18 β-Glycyrrhetinic Acid Inhibits Malignant Progression of Prostate Cancer via Regulation of Autophagy and EMT Induced by PTEN/PI3K/mTOR Pathway.

BACKGROUND: Prostate cancer (PCa) is one of the most common malignancies in men, and its progression is closely related to epithelial-mesenchymal transition (EMT) and autophagy imbalance. 18β-Glycyrrhetinic acid (18β-GA) has been reported to exhibit various anti-tumour activities. This study aims to systematically evaluate the impact of 18β-GA on the malignant biological behaviours of PCa and explore its potential molecular mechanisms.

METHODS: The human PCa cell lines LNCaP and PC-3 were used to evaluate the inhibitory effects of 18β-GA on malignant progression. The potential mechanisms were further explored by assessing EMT markers, autophagy-related proteins and angiogenesis. The role of the PTEN/PI3K/mTOR pathway in 18β-GA's effects was explored through siRNA-mediated PTEN knockdown and Western blot analysis. A PCa xenograft model was established in vivo to assess the impact of 18β-GA on tumour growth.

RESULTS: 18β-GA significantly inhibited the viability, proliferation, migration and invasion of LNCaP and PC-3 cells, while promoting apoptosis, with no significant toxicity to RWPE-1 cells. 18β-GA upregulated E-cadherin and Claudin-1, while downregulating N-cadherin, Vimentin, Snail and MMP2/9, thus inhibiting the EMT process and reducing the angiogenesis capacity and VEGF expression in HUVECs. Additionally, 18β-GA increased the LC3-II/LC3-I ratio, upregulated Beclin1 and ATG7 and downregulated p62, indicating activation of autophagic flux. Mechanistic studies revealed that 18β-GA upregulated PTEN expression and inhibited PI3K and mTOR phosphorylation. PTEN knockdown partially reversed its effects on autophagy, EMT and malignant phenotypes. In vivo experiments further confirmed that 18β-GA significantly suppressed xenograft tumour growth and exhibited anti-tumour effects.

CONCLUSION: 18β-GA inhibits the malignant progression of PCa cells and xenograft tumour growth by upregulating PTEN and inhibiting the PI3K/mTOR axis, synergistically activating autophagy and inhibiting EMT and angiogenesis. 18β-GA holds promise as a potential anti-PCa drug targeting the PTEN/PI3K/mTOR pathway, jointly regulating autophagy and EMT.