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

Eiji Kobayashi1,2, Duhyeong Hwang3, Anjali Bheda-Malge1

  • 1Lineberger Comprehensive Cancer Center, UNC at Chapel Hill, Department of Immunology and Microbiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

International Journal of Molecular Sciences
|August 3, 2019
PubMed

Insights

Small-molecule inhibitors targeting ubiquitin C-terminal hydrolase L1 (UCH-L1) de-ubiquitinating (DUB) activity, including nanoparticle formulations, reduce cancer cell metastasis. These inhibitors decrease pro-metastatic markers and viral factor transfer in squamous cell carcinoma and nasopharyngeal cell lines.

Area of Science:

  • Oncology
  • Molecular Biology
  • Nanotechnology

Background:

  • Ubiquitin C-terminal hydrolase L1 (UCH-L1) is typically found in adult nervous and reproductive systems but is aberrantly expressed in various human cancers.
  • UCH-L1's de-ubiquitinating (DUB) activity is increasingly recognized for its pro-metastatic role in carcinomas.
  • Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC) involves the pro-metastatic protein Latent membrane protein 1 (LMP1).

Purpose of the Study:

  • To investigate the anti-metastatic effects of the UCH-L1 DUB inhibitor LDN-57444 in oral squamous cell carcinoma (OSCC) and EBV-positive nasopharyngeal (NP) cell lines.
  • To develop and evaluate a nanoparticle formulation (LDN-POx) of LDN-57444 to improve its solubility and efficacy.
  • To assess the impact of UCH-L1 inhibition on exosome secretion, pro-metastatic factors, cell motility, and viral factor transfer.

Main Methods:

  • Utilized cell lines from advanced OSCC and invasive NP expressing EBV's LMP1.
  • Developed polyoxazoline micellar nanoparticles (LDN-POx) to formulate LDN-57444.
  • Assessed anti-metastatic effects using in vitro assays measuring cell motility, adhesion, exosome secretion, and pro-metastatic marker levels.

Main Results:

  • LDN-57444 and its nanoparticle formulation LDN-POx demonstrated comparable in vitro anti-metastatic effects.
  • Inhibition of UCH-L1 DUB activity reduced exosome secretion and lowered pro-metastatic factors within exosomal fractions.
  • Treatment suppressed the motility of metastatic squamous carcinoma and EBV-positive NP cells, decreased pro-metastatic markers, reduced cell adhesion, and inhibited LMP1 transfer via extracellular vesicles.

Conclusions:

  • Small-molecule inhibitors of UCH-L1 DUB activity, including soluble nanoparticle formulations like LDN-POx, show significant anti-metastatic potential.
  • Targeting UCH-L1 offers a promising therapeutic strategy for invasive carcinomas, particularly EBV-positive malignancies.
  • LDN-POx represents a viable approach to overcome solubility limitations and deliver UCH-L1 inhibitors for cancer treatment.
Keywords:
de-ubiquitinationmarkers of invasion and metastasisnanoformulationpoly (2-oxazoline) micelle

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