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–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.
Highlights
In the past several years, it has become clear that ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) is an evolutionarily conserved multifunctional protein which is likely to contribute to a number of cellular physiological activities in normal and transformed cells
De novo expression of UCH-L1 has been observed in different types of malignancies [3,4], the function of UCH-L1 in the development of primary tumors remains unclear [3,5,6]: Overexpression of UCH-L1 in in vivo transgenic mouse models induces lymphomas acting as an oncogene [7,8], while in the cell lines and tissue samples from different primary carcinomas the expression of uch-l1 is frequently silenced by promoter methylation, suggesting its potential role as a tumor suppressor [8,9]
UCH-L1 is associated with all major cellular systems involved in membrane trafficking, including extracellular membrane vesicles [23,43,44,45]
Summary
In the past several years, it has become clear that ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) is an evolutionarily conserved multifunctional protein which is likely to contribute to a number of cellular physiological activities in normal and transformed cells. Several cellular targets (direct or indirect) have been identified for UCH-L1 in different types of malignancies: UCH-L1 contributes to p27 (Kip1) degradation via its interaction and nuclear translocation with JAB1 (COPS5) in lung cancer cells [10]; the β-catenin oncogenic pathway is activated by UCH-L1 [11]; UCH-L1 manipulates the mTOR-mediated protein biosynthesis and is required for MYC-driven lymphomagenesis in mice [12]. Tumor viruses such as the Epstein-Barr virus (EBV), human papillomavirus (HPV), and Kaposi’s sarcoma-associated herpesvirus (KSHV) induce UCH-L1 expression during cell transformation [13,14,15,16,17]. Selective inhibition of UCH-L1 DUB activity with the available specific small-molecule inhibitors [25,26] might be valuable for the prevention of metastasis of cancer [3,27]
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