Interaction between NF-κB and PLAC8 impairs autophagy providing a survival advantage to prostate cells transformed by cadmium.

Prostate cancer risk is influenced by various factors, including exposure to heavy metals like cadmium (Cd). The study reveals that the autophagy-regulating gene PLAC8 (placenta-specific 8) is significantly involved in Cd-induced prostate carcinogenesis, and NF-κB acts as the upstream transcriptional activator of PLAC8, which then selectively up-regulates BCL-xL, providing a survival advantage to Cd-transformed cells. NF-κB activation stabilizes PLAC8 in the cytosol, disrupting autophagy by allowing PLAC8 to colocalize with LC3B instead of LAMP1. Silencing NF-κB down-regulates PLAC8 and its survival function while inhibiting NF-κB or PLAC8, which restores autophagy and decreases tumor growth in xenograft models. In addition, targeting BCL-xL confirmed this signaling pathway. The findings suggest that sustained NF-κB activation regulates PLAC8 and highlights the NF-κB-PLAC8-BCL-xL axis as a potential target for early detection and therapies in metal-induced prostate cancer.