1. Inhibition of UCH-L1 Deubiquitinating Activity with Two Forms of LDN-57444 Has Anti-Invasive Effects in Metastatic Carcinoma Cells
- Author
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Mitsuharu Aga, Anjali Bheda-Malge, Marina Sokolsky, Julia Shakelford, Duhyeong Hwang, Satoru Kondo, Eiji Kobayashi, Alexander V. Kabanov, Christopher B. Whitehurst, Tomokazu Yoshizaki, and Joseph S. Pagano
- Subjects
0301 basic medicine ,Herpesvirus 4, Human ,Indoles ,Exosomes ,lcsh:Chemistry ,0302 clinical medicine ,Cell Movement ,Nasopharynx ,Tumor Virus ,Oximes ,markers of invasion and metastasis ,lcsh:QH301-705.5 ,Oxazoles ,Spectroscopy ,Micelles ,Drug Carriers ,Chemistry ,General Medicine ,3. Good health ,Computer Science Applications ,Gene Expression Regulation, Neoplastic ,030220 oncology & carcinogenesis ,Ubiquitin Thiolesterase ,Cell Survival ,Antineoplastic Agents ,Catalysis ,Virus ,Article ,Inorganic Chemistry ,Gene product ,Viral Matrix Proteins ,03 medical and health sciences ,Cell Line, Tumor ,Cell Adhesion ,Humans ,Secretion ,Physical and Theoretical Chemistry ,Molecular Biology ,Cell Proliferation ,Mouth ,poly (2-oxazoline) micelle ,Organic Chemistry ,Epithelial Cells ,nanoformulation ,In vitro ,Microvesicles ,Squamous carcinoma ,de-ubiquitination ,030104 developmental biology ,lcsh:Biology (General) ,lcsh:QD1-999 ,Cell culture ,Cancer research ,Nanoparticles - Abstract
Normally ubiquitin C-terminal hydrolase L1 (UCH-L1) is expressed in the central nervous and reproductive systems of adults, but its de novo expression has been detected in many human cancers. There is a growing body of evidence that UCH-L1 de-ubiquitinating (DUB) activity plays a major pro-metastatic role in certain carcinomas. Here we tested anti-metastatic effects of the small-molecule inhibitor of UCH-L1 DUB activity, LDN-57444, in cell lines from advanced oral squamous cell carcinoma (OSCC) as well as invasive nasopharyngeal (NP) cell lines expressing the major pro-metastatic gene product of Epstein&ndash, Barr virus (EBV) tumor virus, LMP1. To overcome the limited aqueous solubility of LDN-57444 we developed a nanoparticle formulation of LDN-57444 by incorporation of the compound in polyoxazoline micellear nanoparticles (LDN-POx). LDN-POx nanoparticles were equal in effects as the native compound in vitro. Our results demonstrate that inhibition of UCH-L1 DUB activity with LDN or LDN-POx inhibits secretion of exosomes and reduces levels of the pro-metastatic factor in exosomal fractions. Both forms of UCH-L1 DUB inhibitor suppress motility of metastatic squamous carcinoma cells as well as nasopharyngeal cells expressing EBV pro-metastatic Latent membrane protein 1 (LMP1) in physiological assays. Moreover, treatment with LDN and LDN-POx resulted in reduced levels of pro-metastatic markers, a decrease of carcinoma cell adhesion, as well as inhibition of extra-cellular vesicle (ECV)-mediated transfer of viral invasive factor LMP1. We suggest that soluble inhibitors of UCH-L1 such as LDN-POx offer potential forms of treatment for invasive carcinomas including EBV-positive malignancies.
- Published
- 2019