Functionalized Gold Nanoparticles Suppress the Proliferation of Human Lung Alveolar Adenocarcinoma Cells by Deubiquitinating Enzymes Inhibition

Functionalized gold nanoparticles (AuNPs) are widely used in therapeutic applications, but little is known regarding the impact of their surface functionalization in the process of toxicity against cancer cells. This study investigates the anticancer effects of 5 nm spherical AuNPs functionalized with tannate, citrate, and PVP on deubiquitinating enzymes (DUBs) in human lung alveolar adenocarcinoma (A549) cells. Our findings show that functionalized AuNPs reduce the cell viability in a concentration- and time-dependent manner as measured by modified lactate dehydrogenase (mLDH) and 3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assays. An increased generation of intracellular reactive oxygen species (ROS) and depletion of glutathione (GSH/GSSG) ratio was observed with the highest AuNP concentration of 10 μg/mL. The expression of DUBs such as ubiquitin specific proteases (USP7, USP8, and USP10) was slightly inhibited when treated with concentrations above 2.5 μg/mL. Moreover, functionalized AuNPs showed an inhibitory effect on protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) and wingless-related integration site (Wnt) signaling proteins, and this could further trigger mitochondrial related-apoptosis by the upregulation of caspase-3, caspase-9, and PARP in A549 cells. Furthermore, our study shows a mechanistic understanding of how functionalized AuNPs inhibit the DUBs, consequently suppressing cell proliferation, and can be modulated as an approach toward anticancer therapy. The study also warrants the need for future work to investigate the effect of functionalized AuNPs on DUB on other cancer cell lines both in vitro and in vivo.