Next Article in Journal
Genomic Architecture of Phenotypic Plasticity in Response to Water Stress in Tetraploid Wheat
Previous Article in Journal
A Proteomics Analysis of Calmodulin-Binding Proteins in Dictyostelium discoideum during the Transition from Unicellular Growth to Multicellular Development
Article

The Effect of Neddylation Inhibition on Inflammation-Induced MMP9 Gene Expression in Esophageal Squamous Cell Carcinoma

1
Laboratory of Cytobiochemistry, Biotechnology Faculty, University of Wroclaw, 50-383 Wroclaw, Poland
2
Department of Minimally Invasive Surgery and Proctology, Wroclaw Medical University, 50-556 Wroclaw, Poland
3
Second Department and Clinic of General and Oncological Surgery, Wroclaw Medical University, 50-556 Wroclaw, Poland
4
Department of Biochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland
5
Department of Medicine, School of Medicine, Case Western Reserve University, Rammelkamp Center for Research, Cleveland, OH 44109, USA
6
Department of Surgical Education, Wroclaw Medical University, 50-368 Wroclaw, Poland
*
Author to whom correspondence should be addressed.
Academic Editor: Thomas Andl
Int. J. Mol. Sci. 2021, 22(4), 1716; https://doi.org/10.3390/ijms22041716
Received: 11 December 2020 / Revised: 1 February 2021 / Accepted: 3 February 2021 / Published: 9 February 2021
(This article belongs to the Section Molecular Biology)
Inhibition of the protein neddylation process by the small-molecule inhibitor MLN4924 has been recently indicated as a promising direction for cancer treatment. However, the knowledge of all biological consequences of MLN4924 for cancer cells is still incomplete. Here, we report that MLN4924 inhibits tumor necrosis factor-alpha (TNF-α)-induced matrix metalloproteinase 9 (MMP9)-driven cell migration. Using real-time polymerase chain reaction (PCR) and gelatin zymography, we found that MLN4924 inhibited expression and activity of MMP9 at the messenger RNA (mRNA) and protein levels in both resting cells and cells stimulated with TNF-α, and this inhibition was closely related to impaired cell migration. We also revealed that MLN4924, similar to TNF-α, induced phosphorylation of inhibitor of nuclear factor kappa B-alpha (IκB-α). However, contrary to TNF-α, MLN4924 did not induce IκB-α degradation in treated cells. In coimmunoprecipitation experiments, nuclear IκB-α which formed complexes with nuclear factor kappa B p65 subunit (NFκB/p65) was found to be highly phosphorylated at Ser32 in the cells treated with MLN4924, but not in the cells treated with TNF-α alone. Moreover, in the presence of MLN4924, nuclear NFκB/p65 complexes were found to be enriched in c-Jun and cyclin dependent kinase inhibitor 1 A (CDKN1A/p21) proteins. In these cells, NFκB/p65 was unable to bind to the MMP9 gene promoter, which was confirmed by the chromatin immunoprecipitation (ChIP) assay. Taken together, our findings identified MLN4924 as a suppressor of TNF-α-induced MMP9-driven cell migration in esophageal squamous cell carcinoma (ESCC), likely acting by affecting the nuclear ubiquitin–proteasome system that governs NFκB/p65 complex formation and its DNA binding activity in regard to the MMP9 promoter, suggesting that inhibition of neddylation might be a new therapeutic strategy to prevent invasion/metastasis in ESCC patients. View Full-Text
Keywords: neddylation; metalloproteinases; cancer cell migration; TNF-α–NFκB signaling pathway; esophageal squamous cell carcinoma neddylation; metalloproteinases; cancer cell migration; TNF-α–NFκB signaling pathway; esophageal squamous cell carcinoma
Show Figures

Figure 1

MDPI and ACS Style

Hryniewicz-Jankowska, A.; Wierzbicki, J.; Tabola, R.; Stach, K.; Sossey-Alaoui, K.; Augoff, K. The Effect of Neddylation Inhibition on Inflammation-Induced MMP9 Gene Expression in Esophageal Squamous Cell Carcinoma. Int. J. Mol. Sci. 2021, 22, 1716. https://doi.org/10.3390/ijms22041716

AMA Style

Hryniewicz-Jankowska A, Wierzbicki J, Tabola R, Stach K, Sossey-Alaoui K, Augoff K. The Effect of Neddylation Inhibition on Inflammation-Induced MMP9 Gene Expression in Esophageal Squamous Cell Carcinoma. International Journal of Molecular Sciences. 2021; 22(4):1716. https://doi.org/10.3390/ijms22041716

Chicago/Turabian Style

Hryniewicz-Jankowska, Anita, Jaroslaw Wierzbicki, Renata Tabola, Kamilla Stach, Khalid Sossey-Alaoui, and Katarzyna Augoff. 2021. "The Effect of Neddylation Inhibition on Inflammation-Induced MMP9 Gene Expression in Esophageal Squamous Cell Carcinoma" International Journal of Molecular Sciences 22, no. 4: 1716. https://doi.org/10.3390/ijms22041716

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop