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Article

Inhibition of UCH-L1 Deubiquitinating Activity with Two Forms of LDN-57444 Has Anti-Invasive Effects in Metastatic Carcinoma Cells

1
Lineberger Comprehensive Cancer Center, UNC at Chapel Hill, Department of Immunology and Microbiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
2
Center for Nanotechnology in Drug Delivery and Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
3
Laboratory of Chemical Design of Bionanomaterials, Faculty of Chemistry, M.V. Lomonosov Moscow State University, 119992 Moscow, Russia
4
Division of Otolaryngology–Head and Neck Surgery, Graduate School of Medicine, Kanazawa University, Kanazawa 920-8640, Japan
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(15), 3733; https://doi.org/10.3390/ijms20153733
Received: 3 May 2019 / Revised: 26 July 2019 / Accepted: 28 July 2019 / Published: 31 July 2019
(This article belongs to the Section Molecular Oncology)
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–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. View Full-Text
Keywords: de-ubiquitination; markers of invasion and metastasis; poly (2-oxazoline) micelle; nanoformulation de-ubiquitination; markers of invasion and metastasis; poly (2-oxazoline) micelle; nanoformulation
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MDPI and ACS Style

Kobayashi, E.; Hwang, D.; Bheda-Malge, A.; Whitehurst, C.B.; Kabanov, A.V.; Kondo, S.; Aga, M.; Yoshizaki, T.; Pagano, J.S.; Sokolsky, M.; Shakelford, J. Inhibition of UCH-L1 Deubiquitinating Activity with Two Forms of LDN-57444 Has Anti-Invasive Effects in Metastatic Carcinoma Cells. Int. J. Mol. Sci. 2019, 20, 3733. https://doi.org/10.3390/ijms20153733

AMA Style

Kobayashi E, Hwang D, Bheda-Malge A, Whitehurst CB, Kabanov AV, Kondo S, Aga M, Yoshizaki T, Pagano JS, Sokolsky M, Shakelford J. Inhibition of UCH-L1 Deubiquitinating Activity with Two Forms of LDN-57444 Has Anti-Invasive Effects in Metastatic Carcinoma Cells. International Journal of Molecular Sciences. 2019; 20(15):3733. https://doi.org/10.3390/ijms20153733

Chicago/Turabian Style

Kobayashi, Eiji, Duhyeong Hwang, Anjali Bheda-Malge, Christopher B. Whitehurst, Alexander V. Kabanov, Satoru Kondo, Mitsuharu Aga, Tomokazu Yoshizaki, Joseph S. Pagano, Marina Sokolsky, and Julia Shakelford. 2019. "Inhibition of UCH-L1 Deubiquitinating Activity with Two Forms of LDN-57444 Has Anti-Invasive Effects in Metastatic Carcinoma Cells" International Journal of Molecular Sciences 20, no. 15: 3733. https://doi.org/10.3390/ijms20153733

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