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 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2018

Open Access 01-12-2018 | Research

A synthetic cell-penetrating peptide derived from nuclear localization signal of EPS8 exerts anticancer activity against acute myeloid leukemia

Authors: Yiran Chen, Xiaoling Xie, Anqin Wu, Lei Wang, Yuxing Hu, Honghao Zhang, Yuhua Li

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2018

Login to get access

Abstract

Background

Oncogenic roles of epidermal growth factor receptor pathway substrate no.8 (EPS8) have been widely reported in various tumors, making targeting of EPS8 an appealing prospect. Here, we describe the role of EPS8 in acute myeloid leukemia (AML) and consider the potential of EPS8 as an anti-AML target. Nuclear localization signal (NLS) residues of tumor-associated proteins are crucial for cell cycle progression, and specific inhibitors derived from the NLS have inhibitory effect on cancer cells. The NLS in EPS8 has potential as a specific anti-AML target.

Methods

Gene Expression Omnibus expression profiles of AML patients were used to test associations between EPS8 expression and AML patient outcome. The biological characteristics of AML cells after EPS8 knockdown were analyzed in vitro and in vivo. A specific peptide (CP-EPS8-NLS) derived from the NLS of EPS8 (amino acids 298–310) was synthesized, and the anti-AML effects of CP-EPS8-NLS were analyzed in cancer cells and in xenograft models. Mutated CP-EPS8-NLS and penetratin served as controls.

Results

We observed that elevated EPS8 expression in AML patients is associated with poor outcome. Knockdown of EPS8 significantly suppressed the survival of AML cells in vitro and in vivo. CP-EPS8-NLS interfered with EPS8-associated signaling and consequently exerted anti-AML activity. Importantly, CP-EPS8-NLS displayed anti-AML activity in various AML cell types, with diminished activity in PBMCs. CP-ESP8-NLS suppressed U937 cell proliferation, and injection of CP-EPS8-NLS exerted potent antitumor activity in the xenograft tumor models. A synergistic effect of CP-EPS8-NLS and chemotherapeutic agents was also observed in vitro and in vivo. Mechanistically, treatment of various AML cells with CP-EPS8-NLS downregulated the expression of EPS8 and its downstream pathways.

Conclusions

The function of CP-EPS8-NLS is explained by the presence of a NLS in EPS8, which has been shown to induce nuclear translocation, consequently resulting in EPS8 overexpression. These results indicate that EPS8 is a potential target for AML treatment.
Appendix
Available only for authorised users
Literature
1.
2.
3.
Fazioli F, Minichiello L, Matoska V, Castagnino P, Miki T, Wong WT, Di Fiore PP. Eps8, a substrate for the epidermal growth factor receptor kinase, enhances EGF-dependent mitogenic signals. EMBO J. 1993;12:3799–808.PubMedPubMedCentral
4.
5.
Scita G, Tenca P, Areces LB, Tocchetti A, Frittoli E, Giardina G, Ponzanelli I, Sini P, Innocenti M, Di Fiore PP. An effector region in Eps8 is responsible for the activation of the Rac-specific GEF activity of Sos-1 and for the proper localization of the Rac-based actin-polymerizing machine. J Cell Biol. 2001;154:1031–44.CrossRefPubMedPubMedCentral
6.
Castagnino P, Biesova Z, Wong WT, Fazioli F, Gill GN, Di Fiore PP. Direct binding of eps8 to the juxtamembrane domain of EGFR is phosphotyrosine- and SH2-independent. Oncogene. 1995;10:723–9.PubMed
7.
Maa MC, Lee JC, Chen YJ, Chen YJ, Lee YC, Wang ST, Huang CC, Chow NH, Leu TH. Eps8 facilitates cellular growth and motility of colon cancer cells by increasing the expression and activity of focal adhesion kinase. J Biol Chem. 2007;282:19399–409.CrossRefPubMed
8.
Welsch T, Endlich K, Giese T, Buchler MW, Schmidt J. Eps8 is increased in pancreatic cancer and required for dynamic actin-based cell protrusions and intercellular cytoskeletal organization. Cancer Lett. 2007;255:205–18.CrossRefPubMed
9.
Xu M, Shorts-Cary L, Knox AJ, Kleinsmidt-DeMasters B, Lillehei K, Wierman ME. Epidermal growth factor receptor pathway substrate 8 is overexpressed in human pituitary tumors: role in proliferation and survival. Endocrinology. 2009;150:2064–71.CrossRefPubMed
10.
Yap LF, Jenei V, Robinson CM, Moutasim K, Benn TM, Threadgold SP, Lopes V, Wei W, Thomas GJ, Paterson IC. Upregulation of Eps8 in oral squamous cell carcinoma promotes cell migration and invasion through integrin-dependent Rac1 activation. Oncogene. 2009;28:2524–34.CrossRefPubMed
11.
Kang H, Wilson CS, Harvey RC, Chen IM, Murphy MH, Atlas SR, Bedrick EJ, Devidas M, Carroll AJ, Robinson BW, et al. Gene expression profiles predictive of outcome and age in infant acute lymphoblastic leukemia: a Children's oncology group study. Blood. 2012;119:1872–81.CrossRefPubMedPubMedCentral
12.
13.
Ding X, Zhou F, Wang F, Yang Z, Zhou C, Zhou J, Zhang B, Yang J, Wang G, Wei Z, et al. Eps8 promotes cellular growth of human malignant gliomas. Oncol Rep. 2013;29:697–703.CrossRefPubMed
14.
Funato Y, Terabayashi T, Suenaga N, Seiki M, Takenawa T, Miki H. IRSp53/Eps8 complex is important for positive regulation of Rac and cancer cell motility/invasiveness. Cancer Res. 2004;64:5237–44.CrossRefPubMed
15.
Wang H, Teh MT, Ji Y, Patel V, Firouzabadian S, Patel AA, Gutkind JS, Yeudall WA. EPS8 upregulates FOXM1 expression, enhancing cell growth and motility. Carcinogenesis. 2010;31:1132–41.CrossRefPubMedPubMedCentral
16.
Li YH, Xue TY, He YZ, Du JW. Novel oncoprotein EPS8: a new target for anticancer therapy. Future Oncol. 2013;9:1587–94.CrossRefPubMed
17.
He YZ, Liang Z, Wu MR, Wen Q, Deng L, Song CY, Wu BY, Tu SF, Huang R, Li YH. Overexpression of EPS8 is associated with poor prognosis in patients with acute lymphoblastic leukemia. Leuk Res. 2015;39:575–81.CrossRefPubMed
18.
Wang L, Cai SH, Xiong WY, He YJ, Deng L, Li YH. Real-time quantitative polymerase chain reaction assay for detecting the eps8 gene in acute myeloid leukemia. Clin Lab. 2013;59:1261–9.PubMed
19.
Jing Z, Gong L, Xie CY, Zhang L, Su HF, Deng X, Wu SX. Reverse resistance to radiation in KYSE-150R esophageal carcinoma cell after epidermal growth factor receptor signal pathway inhibition by cetuximab. Radiother Oncol. 2009;93:468–73.CrossRefPubMed
20.
Chou TC. Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res. 2010;70:440–6.CrossRefPubMed
21.
Kim D, Lee IH, Kim S, Choi M, Kim H, Ahn S, Saw PE, Jeon H, Lee Y, Jon S. A specific STAT3-binding peptide exerts antiproliferative effects and antitumor activity by inhibiting STAT3 phosphorylation and signaling. Cancer Res. 2014;74:2144–51.CrossRefPubMed
22.
Krawczyk J, Keane N, Swords R, O'Dwyer M, Freeman CL, Giles FJ. Perifosine--a new option in treatment of acute myeloid leukemia? Expert Opin Investig Drugs. 2013;22:1315–27.CrossRefPubMed
23.
Chen YJ, Shen MR, Chen YJ, Maa MC, Leu TH. Eps8 decreases chemosensitivity and affects survival of cervical cancer patients. Mol Cancer Ther. 2008;7:1376–85.CrossRefPubMed
24.
Gorsic LK, Stark AL, Wheeler HE, Wong SS, Im HK, Dolan ME. EPS8 inhibition increases cisplatin sensitivity in lung cancer cells. PLoS One. 2013;8:e82220.CrossRefPubMedPubMedCentral
25.
Chen C, Liang Z, Huang W, Li X, Zhou F, Hu X, Han M, Ding X, Xiang S. Eps8 regulates cellular proliferation and migration of breast cancer. Int J Oncol. 2015;46:205–14.CrossRefPubMed
26.
Logue JS, Cartagena-Rivera AX, Baird MA, Davidson MW, Chadwick RS, Waterman CM. Erk regulation of actin capping and bundling by Eps8 promotes cortex tension and leader bleb-based migration. elife. 2015;4:e08314.CrossRefPubMedPubMedCentral
27.
Maa MC, Hsieh CY, Leu TH. Overexpression of p97Eps8 leads to cellular transformation: implication of pleckstrin homology domain in p97Eps8-mediated ERK activation. Oncogene. 2001;20:106–12.CrossRefPubMed
28.
Wang H, Patel V, Miyazaki H, Gutkind JS, Yeudall WA. Role for EPS8 in squamous carcinogenesis. Carcinogenesis. 2009;30:165–74.CrossRefPubMed
29.
Liu PS, Jong TH, Maa MC, Leu TH. The interplay between Eps8 and IRSp53 contributes to Src-mediated transformation. Oncogene. 2010;29:3977–89.CrossRefPubMed
30.
31.
Barrett D, Brown VI, Grupp SA, Teachey DT. Targeting the PI3K/AKT/mTOR signaling axis in children with hematologic malignancies. Paediatr Drugs. 2012;14:299–316.PubMedPubMedCentral
32.
33.
Chen F, Zhuo X, Qin T, Guo X, Zhang C, Lai L. Designed inhibitor for nuclear localization signal of polo-like kinase 1 induces mitotic arrest. Chem Biol Drug Des. 2017;89:732–40.CrossRefPubMed
34.
Tazzari PL, Cappellini A, Ricci F, Evangelisti C, Papa V, Grafone T, Martinelli G, Conte R, Cocco L, McCubrey JA, Martelli AM. Multidrug resistance-associated protein 1 expression is under the control of the phosphoinositide 3 kinase/Akt signal transduction network in human acute myelogenous leukemia blasts. Leukemia. 2007;21:427–38.CrossRefPubMed
Metadata
Title
A synthetic cell-penetrating peptide derived from nuclear localization signal of EPS8 exerts anticancer activity against acute myeloid leukemia
Authors
Yiran Chen
Xiaoling Xie
Anqin Wu
Lei Wang
Yuxing Hu
Honghao Zhang
Yuhua Li
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2018
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-018-0682-x

Other articles of this Issue 1/2018

Journal of Experimental & Clinical Cancer Research 1/2018 Go to the issue

Research

CDK5RAP3 suppresses Wnt/β-catenin signaling by inhibiting AKT phosphorylation in gastric cancer

Research

Protein phosphatase 2A activation mechanism contributes to JS-K induced caspase-dependent apoptosis in human hepatocellular carcinoma cells

Research

The effects of ultrasound exposure on P-glycoprotein-mediated multidrug resistance in vitro and in vivo

Research

Alternative splicing of human telomerase reverse transcriptase in gliomas and its modulation mediated by CX-5461

Research

SIRT7 suppresses the epithelial-to-mesenchymal transition in oral squamous cell carcinoma metastasis by promoting SMAD4 deacetylation

Research

The putative tumour suppressor miR-1-3p modulates prostate cancer cell aggressiveness by repressing E2F5 and PFTK1
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