Effects of selected deubiquitinating enzyme inhibitors on the proliferation and motility of lung cancer and mesothelioma cell lines

Mirzapoiazova,Tamara; Pozhitkov,Alexander; Nam,Arin; Mambetsariev,Isa; Nelson,Michael  S.; Tan,Yi‑Hung   Carol; Zhang,Keqiang; Raz,Dan; Singhal,Sharad; Nasser,Mohd  W.; Kulkarni,Prakash; Batra,Surinder   K.; Sattler,Martin; Salgia,Ravi

doi:10.3892/ijo.2020.5034

July-2020 Volume 57 Issue 1

Full Size Image

Cover Legend PDF

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

An International Open Access Journal Devoted to General Medicine.

July-2020 Volume 57 Issue 1

Full Size Image

Cover Legend PDF

Article

Effects of selected deubiquitinating enzyme inhibitors on the proliferation and motility of lung cancer and mesothelioma cell lines

Authors:
- Tamara Mirzapoiazova
- Alexander Pozhitkov
- Arin Nam
- Isa Mambetsariev
- Michael S. Nelson
- Yi‑Hung Carol Tan
- Keqiang Zhang
- Dan Raz
- Sharad Singhal
- Mohd W. Nasser
- Prakash Kulkarni
- Surinder K. Batra
- Martin Sattler
- Ravi Salgia
View Affiliations / Copyright

Affiliations: Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA 91010‑3000, USA, Center for Informatics, City of Hope National Medical Center, Duarte, CA 91010‑3000, USA, The Light Microscopy and Digital Imaging Core, Beckman Research Institute, City of Hope, Duarte, CA 91010‑3000, USA, Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, IL 60637, USA, Department of Surgery, City of Hope National Medical Center, Duarte, CA 91010‑3000, USA, Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA, Department of Medical Oncology, Dana‑Farber Cancer Institute, Boston, MA 02215, USA
Pages: 80-86
|
Published online on: April 1, 2020

https://doi.org/10.3892/ijo.2020.5034
Expand metrics +

Abstract

The post‑translational modification of proteins by ubiquitinating enzymes plays a central role in a number of cellular functions, such as cell proteolysis, DNA repair, and cell signaling and communication. Deubiquitinating enzymes (DUBs) disassemble ubiquitin chains and remove ubiquitin moieties from proteins. Targeting DUBs in cancer models has revealed an important role for these enzymes in tumorigenesis, and they therefore have emerged as attractive therapeutic targets. In the present study, the effects of three DUB inhibitors, PR‑619, RA‑9 and LDN‑91946, on a non‑small cell lung cancer cell line (A549) and a mesothelioma cell line (H2373) were investigated. PR‑619 significantly inhibited cell adhesion and the proliferation of both cell lines. RA‑9 exerted an inhibitory effect on the adhesion and proliferation of H2373 cells, whereas it had no effect on A549 cells. Notably, however, while PR‑619 attenuated the proliferation of both cell lines, it exerted an opposite effect on cell motility; in the case of A549 cells, there was a significant increase in cell motility, while for the H2373 cells, there was a significant decrease. Furthermore, protein phosphorylation kinetic analyses revealed that the effects were cell line‑specific. In H2373 cells, the phosphorylation of only one peptide corresponding to the P85A protein was significantly affected, and while LDN‑91946 treatment increased phosphorylation, treatment with RA‑9 or PR‑619 decreased its phosphorylation compared to the DMSO control. By contrast, in the case of A549 cells, the phosphorylation of 21 peptides was significantly affected by the same compounds. In light of the potential for the negative side‑effects of DUB inhibition, such as increased cancer cell motility, the data presented herein underscore the dire need for the development of specific DUB inhibitors and to elucidate the individual role of DUB family members in cancer biology before they can be specifically pharmacologically targeted.

View Figures

View References

1	Kerscher O, Felberbaum R and Hochstrasser M: Modification of proteins by ubiquitin and ubiquitin-like proteins. Annu Rev Cell Dev Biol. 22:159–180. 2006. View Article : Google Scholar : PubMed/NCBI
2	Mansour MA: Ubiquitination: Friend and foe in cancer. Int J Biochem Cell Biol. 101:80–93. 2018. View Article : Google Scholar : PubMed/NCBI
3	Nijman SMB, Luna-Vargas MPA, Velds A, Brummelkamp TR, Dirac AMG, Sixma TK and Bernards R: A genomic and functional inventory of deubiquitinating enzymes. Cell. 123:773–786. 2005. View Article : Google Scholar : PubMed/NCBI
4	Amerik AY and Hochstrasser M: Mechanism and function of deubiquitinating enzymes. Biochim Biophys Acta. 1695:189–207. 2004. View Article : Google Scholar : PubMed/NCBI
5	Poondla N, Chandrasekaran AP, Kim KS and Ramakrishna S: Deubiquitinating enzymes as cancer biomarkers: New therapeutic opportunities? BMB Rep. 52:181–189. 2019. View Article : Google Scholar : PubMed/NCBI
6	Patel K, Ahmed ZS, Huang X, Yang Q, Ekinci E, Neslund-Dudas CM, Mitra B, Elnady FA, Ahn YH, Yang H, et al: Discovering proteasomal deubiquitinating enzyme inhibitors for cancer therapy: Lessons from rational design, nature and old drug reposition. Future Med Chem. 10:2087–2108. 2018. View Article : Google Scholar : PubMed/NCBI
7	Kaushal K, Antao AM, Kim KS and Ramakrishna S: Deubiquitinating enzymes in cancer stem cells: Functions and targeted inhibition for cancer therapy. Drug Discov Today. 23:1974–1982. 2018. View Article : Google Scholar : PubMed/NCBI
8	Yuan T, Yan F, Ying M, Cao J, He Q, Zhu H and Yang B: Inhibition of Ubiquitin-Specific Proteases as a Novel Anticancer Therapeutic Strategy. Front Pharmacol. 9:10802018. View Article : Google Scholar : PubMed/NCBI
9	Harrigan JA, Jacq X, Martin NM and Jackson SP: Deubiquitylating enzymes and drug discovery: Emerging opportunities. Nat Rev Drug Discov. 17:57–78. 2018. View Article : Google Scholar
10	Altun M, Kramer HB, Willems LI, McDermott JL, Leach CA, Goldenberg SJ, Kumar KG, Konietzny R, Fischer R, Kogan E, et al: Activity-based chemical proteomics accelerates inhibitor development for deubiquitylating enzymes. Chem Biol. 18:1401–1412. 2011. View Article : Google Scholar : PubMed/NCBI
11	Issaenko OA and Amerik AY: Chalcone-based small-molecule inhibitors attenuate malignant phenotype via targeting deubiquitinating enzymes. Cell Cycle. 11:1804–1817. 2012. View Article : Google Scholar : PubMed/NCBI
12	Mermerian AH, Case A, Stein RL and Cuny GD: Structure-activity relationship, kinetic mechanism, and selectivity for a new class of ubiquitin C-terminal hydrolase-L1 (UCH-L1) inhibitors. Bioorg Med Chem Lett. 17:3729–3732. 2007. View Article : Google Scholar : PubMed/NCBI
13	D'Arcy P, Wang X and Linder S: Deubiquitinase inhibition as a cancer therapeutic strategy. Pharmacol Ther. 147:32–54. 2015. View Article : Google Scholar
14	Buus R, Faronato M, Hammond DE, Urbé S and Clague MJ: Deubiquitinase activities required for hepatocyte growth factor-induced scattering of epithelial cells. Curr Biol. 19:1463–1466. 2009. View Article : Google Scholar : PubMed/NCBI
15	Lennon FE, Cianci GC, Kanteti R, Riehm JJ, Arif Q, Poroyko VA, Lupovitch E, Vigneswaran W, Husain A, Chen P, et al: Unique fractal evaluation and therapeutic implications of mitochondrial morphology in malignant mesothelioma. Sci Rep. 6:245782016. View Article : Google Scholar : PubMed/NCBI
16	Giaever I and Keese CR: Micromotion of mammalian cells measured electrically. Proc Natl Acad Sci U S A. 88:7896–7900. 1991. View Article : Google Scholar : PubMed/NCBI Erratum. Proc Natl Acad Sci U S A. 90:16341993.
17	Szulcek R, Bogaard HJ and van Nieuw Amerongen GP: Electric cell-substrate impedance sensing for the quantification of endothelial proliferation, barrier function, and motility. J Vis Exp. 85:e513002014.
18	Wegener J, Keese CR and Giaever I: Electric cell-substrate impedance sensing (ECIS) as a noninvasive means to monitor the kinetics of cell spreading to artificial surfaces. Exp Cell Res. 259:158–166. 2000. View Article : Google Scholar : PubMed/NCBI
19	Coughlin K, Anchoori R, Iizuka Y, Meints J, MacNeill L, Vogel RI, Orlowski RZ, Lee MK, Roden RB and Bazzaro M: Small-molecule RA-9 inhibits proteasome-associated DUBs and ovarian cancer in vitro and in vivo via exacerbating unfolded protein responses. Clin Cancer Res. 20:3174–3186. 2014. View Article : Google Scholar : PubMed/NCBI
20	Jonkman JE, Cathcart JA, Xu F, Bartolini ME, Amon JE, Stevens KM and Colarusso P: An introduction to the wound healing assay using live-cell microscopy. Cell Adhes Migr. 8:440–451. 2014. View Article : Google Scholar
21	Kanehisa M, Furumichi M, Tanabe M, Sato Y and Morishima K: KEGG: New perspectives on genomes, pathways, diseases and drugs. Nucleic Acids Res. 45(D1): D353–D361. 2017. View Article : Google Scholar :

Journals

International Journal of Molecular Medicine

International Journal of Oncology

Molecular Medicine Reports

Oncology Reports

Experimental and Therapeutic Medicine

Oncology Letters

Biomedical Reports

Molecular and Clinical Oncology

World Academy of Sciences Journal

International Journal of Functional Nutrition

International Journal of Epigenetics

Medicine International

Effects of selected deubiquitinating enzyme inhibitors on the proliferation and motility of lung cancer and mesothelioma cell lines

This article is mentioned in:

Abstract

Figure 1

Figure 2

Related Articles