Inhibitory effect of Au@Pt-NSs on proliferation, migration, and invasion of EJ bladder carcinoma cells: involvement of cell cycle regulators, signaling pathways, and transcription factor-mediated MMP-9 expression

• Published in: International journal of nanomedicine 2018-01, Vol.13, p.3295-3310
• Main Authors: Shin, Seung-Shick, Noh, Dae-Hwa, Hwang, Byungdoo, Lee, Jo-Won, Park, Sung Lyea, Park, Sung-Soo, Moon, Bokyung, Kim, Wun-Jae, Moon, Sung-Kwon
• Format: Article
• Language: English
• Subjects: Analysis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Aprotinin; Bladder cancer; Cancer metastasis; Cancer therapies; Cancer treatment; Carboplatin; Carcinoma; Cell cycle; Cell Cycle - drug effects; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; Chemotherapy; Cyclin D1 - metabolism; Cyclin-dependent kinases; Cytotoxicity; Deoxyribonucleic acid; DNA; DNA binding proteins; EDTA; Gold - chemistry; Gold - pharmacology; Humans; Kinases; Matrix Metalloproteinase 9 - metabolism; Medical prognosis; Metastasis; Molecular mechanism; Nanomedicine; Nanoparticles; Nanoseeds; Nanostructures - chemistry; NF-kappa B - metabolism; Novels; Nutrition; Original Research; p38 Mitogen-Activated Protein Kinases - metabolism; Patient monitoring equipment; Platinum - chemistry; Platinum - pharmacology; Polyclonal antibodies; Reagents; Signal Transduction - drug effects; Transcription Factors - metabolism; Tumors; Urinary Bladder Neoplasms - drug therapy; Urinary Bladder Neoplasms - pathology
• ISSN: 1178-2013; 1176-9114; 1178-2013
• DOI: 10.2147/IJN.S158463

Although the diverse biological properties of nanoparticles have been studied intensively, research into their mechanism of action is relatively rare. In this study, we investigated the molecular mechanisms of the anticancer activity of heterometallic Au@Pt-nanoseeds (NSs) against bladder cancers. Mode of action of Au@Pt-NSs was investigated through MTT assay, flow cytometry analysis, Western immunoblots, real-time qPCR, wound-healing migration and invasion assays, zymography, and electrophoretic mobility shift assay (EMSA). Treatment with Au@Pt-NSs significantly inhibited the proliferation of EJ cells in a dose-dependent manner by inducing G1 phase cell cycle arrest. Among the regulators associated with the G1 cell cycle phase, CDK2, CDK4, cyclin D1, cyclin E, and p21WAF1 were shown to participate in the inhibitory pathways of Au@Pt-NSs. In addition, treatment with Au@Pt-NSs led to upregulation of phospho-p38 MAPK and downregulation of phospho-AKT in EJ cells. Interestingly, Au@Pt-NSs inhibited the migratory and invasive potential of the cells, which was attributed to the suppression of the enzymatic activity of matrix metalloproteinase-9 (MMP-9). Using MMP-9-specific oligonucleotides, we showed that transcription factors such as NF-κB and Sp-1 were responsible for the MMP-9-mediated metastatic potential of EJ cells. Au@Pt-NSs significantly limited the progression, migration, and invasion of bladder cancer EJ cells. Our data represent a novel insight into developing cisplatin-like chemotherapeutic reagents with fewer side effects and provide useful information on molecular markers to monitor patients under Au@Pt-NSs-based chemotherapy.