Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2019

Open Access 01-12-2019 | Diffuse Large B-Cell Lymphoma | Research

Proteasomal cysteine deubiquitinase inhibitor b-AP15 suppresses migration and induces apoptosis in diffuse large B cell lymphoma

Authors: Liling Jiang, Yuening Sun, Jinxiang Wang, Qingyan He, Xinmei Chen, Xiaoying Lan, Jinghong Chen, Q. Ping Dou, Xianping Shi, Jinbao Liu

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2019

Login to get access

Abstract

Background

The first line therapy for patients with diffuse large B cell (DLBCL) is R-CHOP. About half of DLBCL patients are either refractory to, or will relapse, after the treatment. Therefore, identifying novel drug targets and effective therapeutic agents is urgently needed for improving DLBCL patient survival. b-AP15, a selective small molecule inhibitor of proteasomal USP14 and UCHL5 deubiquitinases (DUBs), has shown selectivity and efficacy in several other types of cancer cells. This is the first study to report the effect of b-AP15 in DLBCL.

Methods

Cell lines of two DLBCL subtypes, Germinal Center B Cell/ GCB (SU-DHL-4, OCI-LY-1, OCI-LY-19) and Activated B Cell/ABC (SU-DHL-2), were used in the current study. Cell viability was measured by MTS assay, proliferation by trypan blue exclusion staining assay, cellular apoptosis by Annexin V-FITC/PI staining and mitochondrial outer membrane permeability assays, the activities of 20S proteasome peptidases by cleavage of specific fluorogenic substrates, and cell migration was detected by transwell assay in these GCB- and ABC-DLBCL cell lines. Mouse xenograft models of SU-DHL-4 and SU-DHL-2 cells were used to determine in vivo effects of b-AP15 in DLBCL tumors.

Results

b-AP15 inhibited proteasome DUB activities and activated cell death pathway, as evident by caspase activation and mitochondria apoptosis in GCB- and ABC- DLBCL cell lines. b-AP15 treatment suppressed migration of GCB- and ABC-DLBCL cells via inhibiting Wnt/β-catenin and TGFβ/Smad pathways. Additionally, b-AP15 significantly inhibited the growth of GCB- and ABC DLBCL in xenograft models.

Conclusions

These results indicate that b-AP15 inhibits cell migration and induces apoptosis in GCB- and ABC-DLBCL cells, and suggest that inhibition of 19S proteasomal DUB should be a novel strategy for DLBCL treatment.
Appendix
Available only for authorised users
Literature
1.
Camicia R, Winkler HC, Hassa PO. Novel drug targets for personalized precision medicine in relapsed/refractory diffuse large B-cell lymphoma: a comprehensive review. Mol Cancer. 2015;14:207.CrossRef
2.
Schneider C, Pasqualucci L, Dalla-Favera R. Molecular pathogenesis of diffuse large B-cell lymphoma. Semin Diagn Pathol. 2011;28(2):167–77.CrossRef
3.
Martelli M, Ferreri AJ, Agostinelli C, Di Rocco A, Pfreundschuh M, Pileri SA. Diffuse large B-cell lymphoma. Crit Rev Oncol Hematol. 2013;87(2):146–71.CrossRef
4.
Shipp MA. Molecular signatures define new rational treatment targets in large B-cell lymphomas. Hematology Am Soc Hematol Educ Program 2007, ASH Education Book. 2007;2007(1):265–9CrossRef
5.
Lenz G, Wright GW, Emre NC, Kohlhammer H, Dave SS, Davis RE, Carty S, Lam LT, Shaffer AL, Xiao W, et al. Molecular subtypes of diffuse large B-cell lymphoma arise by distinct genetic pathways. Proc Natl Acad Sci U S A. 2008;105(36):13520–5.CrossRef
6.
Iqbal J, Sanger WG, Horsman DE, Rosenwald A, Pickering DL, Dave B, Dave S, Xiao L, Cao K, Zhu Q, et al. BCL2 translocation defines a unique tumor subset within the germinal center B-cell-like diffuse large B-cell lymphoma. Am J Pathol. 2004;165(1):159–66.CrossRef
7.
Nogai H, Wenzel SS, Hailfinger S, Grau M, Kaergel E, Seitz V, Wollert-Wulf B, Pfeifer M, Wolf A, Frick M, et al. IkappaB-zeta controls the constitutive NF-kappaB target gene network and survival of ABC DLBCL. Blood. 2013;122(13):2242–50.CrossRef
8.
Roschewski M, Staudt LM, Wilson WH. Diffuse large B-cell lymphoma-treatment approaches in the molecular era. Nat Rev Clin Oncol. 2014;11(1):12–23.CrossRef
9.
Coiffier B. Rituximab in the treatment of diffuse large B-cell lymphomas. Semin Oncol. 2002;29(1 Suppl 2):30–5.CrossRef
10.
Lenz G, Staudt LM. Aggressive lymphomas. N Engl J Med. 2010;362(15):1417–29.CrossRef
11.
Abramson JS. Hitting back at lymphoma: how do modern diagnostics identify high-risk diffuse large B-cell lymphoma subsets and alter treatment? Cancer-Am Cancer Soc. 2019;125(18):3111–20.
12.
Chauhan D, Catley L, Li G, Podar K, Hideshima T, Velankar M, Mitsiades C, Mitsiades N, Yasui H, Letai A, et al. A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib. Cancer Cell. 2005;8(5):407–19.CrossRef
13.
Harousseau JL, Attal M. How I treat first relapse of myeloma. Blood. 2017;130(8):963–73.CrossRef
14.
Xiao Z, Zhang P, Ma L. The role of deubiquitinases in breast cancer. Cancer Metastasis Rev. 2016;35(4):589–600.CrossRef
15.
Chen X, Yang Q, Xiao L, Tang D, Dou QP, Liu J. Metal-based proteasomal deubiquitinase inhibitors as potential anticancer agents. Cancer Metastasis Rev. 2017;36(4):655–68.CrossRef
16.
D'Arcy P, Linder S. Proteasome deubiquitinases as novel targets for cancer therapy. Int J Biochem Cell Biol. 2012;44(11):1729–38.CrossRef
17.
D'Arcy P, Wang X, Linder S. Deubiquitinase inhibition as a cancer therapeutic strategy. PharmacolTher. 2015;147:32–54.
18.
Shinji S, Naito Z, Ishiwata S, Ishiwata T, Tanaka N, Furukawa K, Suzuki H, Seya T, Matsuda A, Katsuta M, et al. Ubiquitin-specific protease 14 expression in colorectal cancer is associated with liver and lymph node metastases. Oncol Rep. 2006;15(3):539–43.PubMed
19.
Mines MA, Goodwin JS, Limbird LE, Cui FF, Fan GH. Deubiquitination of CXCR4 by USP14 is critical for both CXCL12-induced CXCR4 degradation and chemotaxis but not ERK ativation. J Biol Chem. 2009;284(9):5742–52.CrossRef
20.
Wicks SJ, Haros K, Maillard M, Song L, Cohen RE, Dijke PT, Chantry A. The deubiquitinating enzyme UCH37 interacts with Smads and regulates TGF-beta signalling. Oncogene. 2005;24(54):8080–4.CrossRef
21.
Chen Y, Fu D, Xi J, Ji Z, Liu T, Ma Y, Zhao Y, Dong L, Wang Q, Shen X. Expression and clinical significance of UCH37 in human esophageal squamous cell carcinoma. Dig Dis Sci. 2012;57(9):2310–7.CrossRef
22.
Delforoush M, Berglund M, Edqvist PH, Sundstrom C, Gullbo J, Enblad G. Expression of possible targets for new proteasome inhibitors in diffuse large B-cell lymphoma. Eur J Haematol. 2017;98(1):52–6.CrossRef
23.
D'Arcy P, Brnjic S, Olofsson MH, Fryknas M, Lindsten K, De Cesare M, Perego P, Sadeghi B, Hassan M, Larsson R, et al. Inhibition of proteasome deubiquitinating activity as a new cancer therapy. Nat Med. 2011;17(12):1636–40.CrossRef
24.
Tian Z, D'Arcy P, Wang X, Ray A, Tai YT, Hu Y, Carrasco RD, Richardson P, Linder S, Chauhan D, et al. A novel small molecule inhibitor of deubiquitylating enzyme USP14 and UCHL5 induces apoptosis in multiple myeloma and overcomes bortezomib resistance. Blood. 2014;123(5):706–16.CrossRef
25.
Chitta K, Paulus A, Akhtar S, Blake MK, Caulfield TR, Novak AJ, Ansell SM, Advani P, Ailawadhi S, Sher T, et al. Targeted inhibition of the deubiquitinating enzymes, USP14 and UCHL5, induces proteotoxic stress and apoptosis in Waldenstrommacroglobulinaemiatumour cells. Br J Haematol. 2015;169(3):377–90.CrossRef
26.
Shi X, Jin Y, Cheng C, Zhang H, Zou W, Zheng Q, Lu Z, Chen Q, Lai Y, Pan J. Triptolide inhibits Bcr-Abl transcription and induces apoptosis in STI571-resistant chronic myelogenous leukemia cells harboring T315I mutation. Clin Cancer Res. 2009;15(5):1686–97.CrossRef
27.
Wang C, Youle RJ. The role of mitochondria in apoptosis*. Annu Rev Genet. 2009;43:95–118.CrossRef
28.
Ruiduo C, Ying D, Qiwei W. CXCL9 promotes the progression of diffuse large B-cell lymphoma through up-regulating beta-catenin. Biomed Pharmacother. 2018;107:689–95.CrossRef
29.
Li Q, Liu X, Zhao C. Smad4 gene silencing enhances the chemosensitivity of human lymphoma cells to adriamycin via inhibition of the activation of transforming growth factor beta signaling pathway. J Cell Biochem. 2019;120(9):15098–105.CrossRef
30.
Jung H, Kim BG, Han WH, Lee JH, Cho JY, Park WS, Maurice MM, Han JK, Lee MJ, Finley D, et al. Deubiquitination of Dishevelled by Usp14 is required for Wnt signaling. ONCOGENESIS. 2013;2:e64.CrossRef
31.
Wicks SJ, Grocott T, Haros K, Maillard M, Ten DP, Chantry A. Reversible ubiquitination regulates the Smad/TGF-beta signalling pathway. Biochem Soc Trans. 2006;34(Pt 5):761–3.CrossRef
32.
Strauss SJ, Higginbottom K, Juliger S, Maharaj L, Allen P, Schenkein D, Lister TA, Joel SP. The proteasome inhibitor bortezomib acts independently of p53 and induces cell death via apoptosis and mitotic catastrophe in B-cell lymphoma cell lines. Cancer Res. 2007;67(6):2783–90.CrossRef
33.
Fuchs O. Targeting of NF-kappaB signaling pathway, other signaling pathways and epigenetics in therapy of multiple myeloma. Cardiovasc HematolDisord Drug Targets. 2013;13(1):16–34.CrossRef
34.
Dunleavy K, Pittaluga S, Czuczman MS, Dave SS, Wright G, Grant N, Shovlin M, Jaffe ES, Janik JE, Staudt LM, et al. Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma. Blood. 2009;113(24):6069–76.CrossRef
35.
Cai J, Xia X, Liao Y, Liu N, Guo Z, Chen J, Yang L, Long H, Yang Q, Zhang X, et al. A novel deubiquitinase inhibitor b-AP15 triggers apoptosis in both androgen receptor-dependent and -independent prostate cancers. Oncotarget. 2017;8(38):63232–46.CrossRef
36.
Corcelle E, Djerbi N, Mari M, Nebout M, Fiorini C, Fenichel P, Hofman P, Poujeol P, Mograbi B. Control of the autophagy maturation step by the MAPK ERK and p38: lessons from environmental carcinogens. Autophagy. 2007;3(1):57–9.CrossRef
37.
Zhang B, Li M, Huang P, Guan XY, Zhu YH. Overexpression of ubiquitin specific peptidase 14 predicts unfavorable prognosis in esophageal squamous cell carcinoma. Thorac Cancer. 2017;8(4):344–9.CrossRef
38.
Wang L, Chen YJ, Xu K, Wang YY, Shen XZ, Tu RQ. High expression of UCH37 is significantly associated with poor prognosis in human epithelial ovarian cancer. Tumour Biol. 2014;35(11):11427–33.CrossRef
39.
Nan L, Jacko AM, Tan J, Wang D, Zhao J, Kass DJ, Ma H, Zhao Y. Ubiquitin carboxyl-terminal hydrolase-L5 promotes TGFbeta-1 signaling by de-ubiquitinating and stabilizing Smad2/Smad3 in pulmonary fibrosis. Sci Rep. 2016;6:33116.CrossRef
Metadata
Title
Proteasomal cysteine deubiquitinase inhibitor b-AP15 suppresses migration and induces apoptosis in diffuse large B cell lymphoma
Authors
Liling Jiang
Yuening Sun
Jinxiang Wang
Qingyan He
Xinmei Chen
Xiaoying Lan
Jinghong Chen
Q. Ping Dou
Xianping Shi
Jinbao Liu
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2019
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-019-1446-y

Other articles of this Issue 1/2019

Journal of Experimental & Clinical Cancer Research 1/2019 Go to the issue

Research

SHMT1 inhibits the metastasis of HCC by repressing NOX1-mediated ROS production

Research

Systematic analysis of NLMP suggests nuclear localization of RTK/MET kinases resemble cancer cell clearance

Research

Methylation-mediated silencing of miR-133a-3p promotes breast cancer cell migration and stemness via miR-133a-3p/MAML1/DNMT3A positive feedback loop

Research

AKR1C1 controls cisplatin-resistance in head and neck squamous cell carcinoma through cross-talk with the STAT1/3 signaling pathway

Research

CRABP2 regulates invasion and metastasis of breast cancer through hippo pathway dependent on ER status

Research

ACE2 inhibits breast cancer angiogenesis via suppressing the VEGFa/VEGFR2/ERK pathway
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits