Ferroptosis modulates invasion and migration in prostate cancer PC-3M subclones
Year: 2025
Type: article
Abstract: Prostate cancer (PCa) metastasis remains a formidable clinical challenge, underscoring the urgent need to uncover its underlying molecular mechanisms. Leveraging the PC-3M cell line and its sublines with divergent metastatic potentials (PC-3M-1E8, highly metastatic; PC-3M-2B4, low-metastatic), this study investigated the role of ferroptosis, a form of iron-dependent regulated cell death, in PCa metastasis. Functional assays demonstrated that PC-3M-1E8 cells exhibited significantly enhanced proliferation, migration, invasion, and clonogenic capacity compared to PC-3M-2B4 cells. Proteomic analysis identified 5,502 differentially expressed proteins, with GSEA pinpointing ferroptosis as the most significantly enriched pathway (NES = 2.8, FDR < 0.001) in PC-3M-1E8 cells. Key ferroptosis regulators, including GPX4 (1.4-fold), GCLM (1.6-fold), GCLC (1.5-fold), and TFRC (1.8-fold), were upregulated in PC-3M-1E8, while ACSL4 (0.7-fold) and VDAC3 (0.6-fold) were downregulated, constructing a ferroptosis-resistant network. Functional validation revealed that PC-3M-1E8 cells were more resistant to ferroptosis induction, evidenced by 3.68-fold higher GPX4 expression, 1.37-fold elevated GSH/GSSG ratios, and blunted iron responses. These findings establish an inverse correlation between ferroptosis sensitivity and PCa metastatic potential, providing a novel perspective on PCa metastasis by linking iron metabolism reprogramming to metastatic competence. Clinically, the identified ferroptosis-related signatures offer potential as predictive biomarkers for metastatic risk, and ferroptosis induction emerges as a promising therapeutic strategy for metastatic PCa. Future research should focus on exploring the crosstalk between ferroptosis and other cancer-related pathways to develop more effective targeted therapies. • Highly metastatic prostate cancer cells exhibit ferroptosis resistance, inversely correlating with metastatic potential. • A ferroptosis-resistant network is established via upregulation (GPX4, GCLC, GCLM, TFRC) and downregulation (ACSL4, VDAC3) of key regulators. • Ferroptosis-related signatures offer predictive biomarker potential, and ferroptosis induction represents a therapeutic vulnerability for metastatic prostate cancer.
Source: Experimental Cell Research
Institution: Fudan University
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,270
Award: G2979007768
OpenAlex ID: W4416817748