L-cysteine selenium nanoparticles induce apoptosis in ovarian cancer cells by activating the FOXO3a/GADD45A pathway.
TL;DR
L-SeNPs exert potent antitumor effects in ovarian cancer cells by inducing ROS-mediated DNA damage and activating the FOXO3a-GADD45A axis, thereby triggering mitochondrial apoptosis and suppressing tumor cell proliferation.
Abstract
Selenium nanoparticles (SeNPs) have emerged as promising anticancer agents due to their selective cytotoxicity and ability to modulate oncogenic signaling pathways. In this study, we developed a novel L-cysteine-modified selenium nanoparticles (L-SeNPs) system and investigated its antitumor effects and underlying molecular mechanisms in ovarian cancer cells. Our results demonstrated that L-SeNPs significantly inhibited cell proliferation and clonogenic potential in a dose- and time-dependent manner in A2780 and SKOV3 ovarian cancer cells. Mechanistically, L-SeNPs induced intracellular reactive oxygen species (ROS) accumulation, which subsequently resulted in DNA damage, as indicated by the accumulation of γ-H2AX. Treatment with the ROS scavenger N-acetyl-L-cysteine (NAC) markedly attenuated L-SeNPs-induced DNA damage, indicating that ROS generation serves as an upstream event in this process. L-SeNPs further triggered mitochondrial apoptosis characterized by activation of Bax, Bak, and cleaved PARP-1, along with downregulation of Bcl-2. Transcriptomic profiling revealed significant enrichment of the FOXO signaling pathway following L-SeNPs treatment, with GADD45A identified as a key upregulated downstream effector. Further mechanistic studies demonstrated that ROS-mediated DNA damage promoted FOXO3a nuclear translocation, leading to transcriptional activation of GADD45A. Functional experiments confirmed that both FOXO3a and GADD45A are essential for L-SeNPs-induced apoptosis, and restoration of GADD45A partially rescued apoptotic activity in FOXO3a-silenced cells, indicating that GADD45A acts downstream of FOXO3a. In conclusion, L-SeNPs exert potent antitumor effects in ovarian cancer cells by inducing ROS-mediated DNA damage and activating the FOXO3a-GADD45A axis, thereby triggering mitochondrial apoptosis and suppressing tumor cell proliferation. These findings provide new mechanistic insights into selenium-based nanomaterials and suggest the FOXO3a-GADD45A pathway as a potential therapeutic target for ovarian cancer treatment.