Tissue Inhibitor of Metalloproteinase 1 promotes ferroptosis and suppresses prostate cancer metastasis.

Abstract

Tissue inhibitor of metalloproteinase 1 (TIMP1) has been implicated in prostate cancer metastasis. In this study, PC-3M-2B4 cells with TIMP1 knockdown (PC-3M-2B4-shTIMP1) or over-expression (PC-3M-2B4-TIMP1) were generated and an inverse correlation was found between TIMP1 expression and cell migration and invasion which was confirmed in vitro and in vivo. Differential TIMP1 expression was accompanied by variations in the expression of the ferroptosis-related proteins, glutathione peroxidase 4 (GPX4), transferrin receptor (TFRC), transferrin (TF), glutamine cysteine ligase catalytic subunit (GCLC) and glutamine cysteine ligase modifier subunit (GCLM). In comparison with TIMP1-overexpressing cells, TIMP1-knockdown cells demonstrated a 12.3% decrease in Fe²⁺ concentration after erastin treatment, a 37.8% reduction in malondialdehyde (MDA) levels, an 113.7% increase in GPX4 expression, and a 78.9% rise in the GSH/GSSG ratio. Our findings indicate that TIMP1 overexpression promotes ferroptosis by modulating critical markers such as GPX4 and TFRC, thereby significantly reducing metastatic potential in prostate cancer cells. Our results highlight TIMP1's role in regulating ferroptosis pathways, which are crucial for tumor progression, and exposes a potential therapeutic target for prostate cancer management.