Titania Nanosheet Generates Peroxynitrite-Dependent S-Nitrosylation and Enhances p53 Function in Lung Cancer Cells

Abstract

Metal nanomaterials can enhance the efficacy of current cancer therapies. Here, we show that Ti0.8O2 nanosheets cause cytotoxicity in several lung cancer cells but not in normal cells. The nanosheet-treated cells showed certain apoptosis characteristics. Protein analysis further indicated the activation of the p53-dependent death mechanism. Transmission electron microscopy (TEM) and scanning electron microscopy (SEM) analyses revealed the cellular uptake of the nanosheets and the induction of cell morphological change. The nanosheets also exhibited a substantial apoptosis effect on drug-resistant metastatic primary lung cancer cells, and it was found that the potency of the nanosheets was dramatically higher than standard drugs. Ti0.8O2 nanosheets induce apoptosis through a molecular mechanism involving peroxynitrite (ONOO−) generation. As peroxynitrite is known to be a potent inducer of S-nitrosylation, we further found that the nanosheets mediated the S-nitrosylation of p53 at C182, resulting in higher protein-protein complex stability, and this was likely to induce the surrounding residues, located in the interface region, to bind more strongly to each other. Molecular dynamics analysis revealed that S-nitrosylation stabilized the p53 dimer with a ΔGbindresidue of <−1.5 kcal/mol. These results provide novel insight on the apoptosis induction effect of the nanosheets via a molecular mechanism involving S-nitrosylation of the p53 protein, emphasizing the mechanism of action of nanomaterials for cancer therapy.

Pillars and Gaps of S-Nitrosylation-Dependent Epigenetic Regulation in Physiology and Cancer

“…p53 is another TF whose nitrosylation may enhance protein stability. Indeed, nitrosative stress induced by metal nanomaterials provides p53 nitrosylation, increases p53 stability, and induces a pro-apoptotic pathway in lung cancer cells [149].…”

Ciprofloxacin-Loaded Titanium Nanotubes Coated with Chitosan: A Promising Formulation with Sustained Release and Enhanced Antibacterial Properties

“…To overcome the limitations of conventional drugs, such as limited solubility (hydrophobic and water-insoluble), failure to selectively target the disease site, adverse effects, and undesirable pharmacodynamics, many studies have been conducted in recent years toward developing more effective drug delivery systems, highlighting the importance of a high level of biocompatibility, loading capacity, and unique structural properties [7,8]. Titanium (Ti) and its alloys, which are currently used in clinical surgeries, are promising candidates for this purpose, as they are extremely durable, nonreactive to human tissues (e.g., dental and bone), and incompatible with living tissue [9][10][11][12]. Despite these, they can neither form strong bonds with bone during the early stages of osseointegration, nor carry/deliver bioactive agents and provide sustained release.…”

“…Titanium (Ti) and its alloys, which are currently used in clinical surgeries, are promising candidates for this purpose, as they are extremely durable, nonreactive to human tissues (e.g., dental and bone), and incompatible with living tissue [ 9 , 10 , 11 , 12 ]. Despite these, they can neither form strong bonds with bone during the early stages of osseointegration, nor carry/deliver bioactive agents and provide sustained release.…”