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

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Medical Oncology
Published in: Medical Oncology 4/2012

01-12-2012 | Review Article

Mechanisms of Apoptin-induced cell death

Authors: Suna Zhou, Mingxin Zhang, Jia Zhang, Hui Shen, Ermek Tangsakar, Jiansheng Wang

Published in: Medical Oncology | Issue 4/2012

Login to get access

Abstract

Apoptin, a 13.6-kD protein encoded by chicken anemia virus, is paid more and more attention, since it selectively induces apoptosis in tumor cells while abolishes cytotoxic effect in normal cells. In addition, Apoptin shows different localization in tumor cells and normal cells: it predominantly accumulates in nucleus of tumor cells, whereas in normal cells, it is detected mainly in cytoplasm. There are various mechanisms implicated in the program of Apoptin-mediated cell death. Up to now, the interpretations have been recognized including that the particular domains control nucleocytoplasmic shuttling of Apoptin, phosphorylation on specific residue and varies relevant signaling contribute to Apoptin’s activity, and the partners interacted with Apoptin regulate activity or subcellular localization of Apoptin. In this review, we make a comprehensive survey of the existing evidence about mechanisms of Apoptin’s action, which might provide scientific basis to make progress in novel targeted tumor therapy.
Literature
1.
Noteborn MH, Todd D, Verschueren CA, de Gauw HW, Curran WL, et al. A single chicken anemia virus protein induces apoptosis. J Virol. 1994;68(1):346–51.PubMed
2.
Maddika S, Mendoza FJ, Hauff K, Zamzow CR, Paranjothy T, et al. Cancer-selective therapy of the future: apoptin and its mechanism of action. Cancer Biol Ther. 2006;5(1):10–9.PubMedCrossRef
3.
Noteborn MH. Chicken anemia virus induced apoptosis: underlying molecular mechanisms. Vet Microbiol. 2004;98(2):89–94.PubMedCrossRef
4.
Backendorf C, Visser AE, de Boer AG, Zimmerman R, Visser M, et al. Apoptin: therapeutic potential of an early sensor of carcinogenic transformation. Annu Rev Pharmacol Toxicol. 2008;48:143–69.PubMedCrossRef
5.
Li X, Jin N, Mi Z, Lian H, Sun L, et al. Antitumor effects of a recombinant fowlpox virus expressing Apoptin in vivo and in vitro. Int J Cancer. 2006;119(12):2948–57.PubMedCrossRef
6.
Lian H, Jin N, Li X, Mi Z, Zhang J, et al. Induction of an effective anti-tumor immune response and tumor regression by combined administration of IL-18 and Apoptin. Cancer Immunol Immunother. 2007;56(2):181–92.PubMedCrossRef
7.
Tavassoli M, Guelen L, Luxon BA, Gäken J. Apoptin: specific killer of tumor cells? Apoptosis. 2005;10(4):717–24.PubMedCrossRef
8.
Olijslagers SJ, Zhang YH, Backendorf C, Noteborn MH. Additive cytotoxic effect of Apoptin and chemotherapeutic agents paclitaxel and etoposide on human tumour cells. Basic Clin Pharmacol Toxicol. 2007;100(2):127–31.PubMed
9.
Pan Y, Fang L, Fan H, Luo R, Zhao Q, et al. Antitumor effects of a recombinant pseudotype baculovirus expressing Apoptin in vitro and in vivo. Int J Cancer. 2010;126(11):2741–51.PubMed
10.
Jin JL, Gong J, Yin TJ, Lu YJ, Xia JJ, et al. PTD4-apoptin protein and dacarbazine show a synergistic antitumor effect on B16-F1 melanoma in vitro and in vivo. Eur J Pharmacol. 2011;654(1):17–25.PubMedCrossRef
11.
Olijslagers S, Dege AY, Dinsart C, Voorhoeve M, Rommelaere J, et al. Potentiation of a recombinant oncolytic parvovirus by expression of Apoptin. Cancer Gene Ther. 2001;8(12):958–65.PubMedCrossRef
12.
Yu CM, Xu HT, Du J. Recombinant Apoptin gene retrovirus induces apoptosis in human breast cancer cells 435. Chin J Cancer Res. 2009;21(3):194–201.CrossRef
13.
Li X, Liu Y, Wen Z, Li C, Lu H, et al. Potent anti-tumor effects of a dual specific oncolytic adenovirus expressing Apoptin in vitro and in vivo. Mol Cancer. 2010;9:10.PubMedCrossRef
14.
Noteborn MH, de Boer GF, van Roozelaar DJ, Karreman C, Kranenburg O, et al. Characterization of cloned chicken anemia virus DNA that contains all elements for the infectious replication cycle. J Virol. 1991;65(6):3131–9.PubMed
15.
Danen-Van Oorschot AA, Zhang YH, Leliveld SR, Rohn JL, Seelen MC, et al. Importance of nuclear localization of apoptin for tumor-specific induction of apoptosis. J Biol Chem. 2003;278(30):27729–36.PubMedCrossRef
16.
Kuusisto HV, Wagstaff KM, Alvisi G, Jans DA. The C-terminus of Apoptin represents a unique tumor cell-enhanced nuclear targeting module. Int J Cancer. 2008;123(12):2965–9.PubMedCrossRef
17.
Wang QM, Fan GC, Chen JZ, Chen HP, He FC. A putative NES mediates cytoplasmic localization of Apoptin in normal cells. Acta Biochim Biophys Sin (Shanghai). 2004;36(12):817–23.CrossRef
18.
Wadia JS, Wagner MV, Ezhevsky SA, Dowdy SF. Apoptin/VP3 contains a concentration-dependent nuclear localization signal (NLS), not a tumorigenic selective NLS. J Virol. 2004;78(11):6077–8.PubMedCrossRef
19.
Poon IK, Oro C, Dias MM, Zhang J, Jans DA. Apoptin nuclear accumulation is modulated by a CRM1-recognized nuclear export signal that is active in normal but not in tumor cells. Cancer Res. 2005;65(16):7059–64.PubMedCrossRef
20.
Heckl S, Regenbogen M, Sturzu A, Gharabaghi A, Feil G, et al. Value of apoptin’s 40-amino-acid C-terminal fragment for the differentiation between human tumor and non-tumor cells. Apoptosis. 2008;13(4):495–508.PubMedCrossRef
21.
Rohn JL, Zhang YH, Aalbers RI, Otto N, Den Hertog J, et al. A tumor-specific kinase activity regulates the viral death protein Apoptin. J Biol Chem. 2002;277(52):50820–7.PubMedCrossRef
22.
Lee YH, Cheng CM, Chang YF, Wang TY, Yuo CY. Apoptin T108 phosphorylation is not required for its tumor-specific nuclear localization but partially affects its apoptotic activity. Biochem Biophys Res Commun. 2007;354(2):391–5.PubMedCrossRef
23.
Heilman DW, Teodoro JG, Green MR. Apoptin nucleocytoplasmic shuttling is required for cell type-specific localization, apoptosis, and recruitment of the anaphase-promoting complex/cyclosome to PML bodies. J Virol. 2006;80(15):7535–45.PubMedCrossRef
24.
Lowe SW, Ruley HE, Jacks T, Housman DE. p53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell. 1993;74(6):957–67.PubMedCrossRef
25.
Warters RL. Radiation-induced apoptosis in a murine T-cell hybridoma. Cancer Res. 1992;52(4):883–90.PubMed
26.
Zhuang SM, Shvarts A, van Ormondt H, Jochemsen AG, van der Eb AJ, et al. Apoptin, a protein derived from chicken anemia virus, induces p53-independent apoptosis in human osteosarcoma cells. Cancer Res. 1995;55(3):486–9.PubMed
27.
28.
Danen-Van Oorschot AA, Zhang Y, Erkeland SJ, Fischer DF, van der Eb AJ, et al. The effect of Bcl-2 on Apoptin in ‘normal’ vs transformed human cells. Leukemia. 1999;13(Suppl 1):S75–7.PubMedCrossRef
29.
Cheng EH, Kirsch DG, Clem RJ, Ravi R, Kastan MB, et al. Conversion of Bcl-2 to a Bax-like death effector by caspases. Science. 1997;278(5345):1966–8.PubMedCrossRef
30.
Schoop RA, Kooistra K, Baatenburg De Jong RJ, Noteborn MH. Bcl-xL inhibits p53- but not Apoptin-induced apoptosis in head and neck squamous cell carcinoma cell line. Int J Cancer. 2004;109(1):38–42.PubMedCrossRef
31.
Danen-van Oorschot AA, van Der Eb AJ, Noteborn MH. The chicken anemia virus-derived protein Apoptin requires activation of caspases for induction of apoptosis in human tumor cells. J Virol. 2000;74(15):7072–8.PubMedCrossRef
32.
Pietersen AM, Rutjes SA, van Tongeren J, Vogels R, Wesseling JG, et al. The tumor-selective viral protein Apoptin effectively kills human biliary tract cancer cells. J Mol Med (Berl). 2004;82(1):56–63.CrossRef
33.
Schoop RA, Verdegaal EM, Baatenburg de Jong RJ, Noteborn MH. Apoptin enhances radiation-induced cell death in poorly responding head and neck squamous cell carcinoma cells. Basic Clin Pharmacol Toxicol. 2010;106(2):130–4.PubMedCrossRef
34.
35.
Maddika S, Bay GH, Kroczak TJ, Ande SR, Maddika S, et al. Akt is transferred to the nucleus of cells treated with Apoptin, and it participates in Apoptin-induced cell death. Cell Prolif. 2007;40(6):835–48.PubMedCrossRef
36.
Jänicke RU, Sohn D, Essmann F, Schulze-Osthoff K. The multiple battles fought by anti-apoptotic p21. Cell Cycle. 2007;6(4):407–13.PubMedCrossRef
37.
Maddika S, Panigrahi S, Wiechec E, Wesselborg S, Fischer U, et al. Unscheduled Akt-triggered activation of cyclin-dependent kinase 2 as a key effector mechanism of Apoptin’s anticancer toxicity. Mol Cell Biol. 2009;29(5):1235–48.PubMedCrossRef
38.
Liu X, Zeidan YH, Elojeimy S, Holman DH, El-Zawahry AM, et al. Involvement of sphingolipids in Apoptin-induced cell killing. Mol Ther. 2006;14(5):627–36.PubMedCrossRef
39.
Liu X, Elojeimy S, El-Zawahry AM, Holman DH, Bielawska A, et al. Modulation of ceramide metabolism enhances viral protein Apoptin’s cytotoxicity in prostate cancer. Mol Ther. 2006;14(5):637–46.PubMedCrossRef
40.
Ogretmen B, Hannun YA. Biologically active sphingolipids in cancer pathogenesis and treatment. Nat Rev Cancer. 2004;4(8):604–16.PubMedCrossRef
41.
Charruyer A, Grazide S, Bezombes C, Müller S, Laurent G, et al. UV-C light induces raft-associated acid sphingomyelinase and JNK activation and translocation independently on a nuclear signal. J Biol Chem. 2005;280(19):19196–204.PubMedCrossRef
42.
Loidl A, Claus R, Ingolic E, Deigner HP, Hermetter A. Role of ceramide in activation of stress-associated MAP kinases by minimally modified LDL in vascular smooth muscle cells. Biochim Biophys Acta. 2004;1690(2):150–8.PubMedCrossRef
43.
Maddika S, Booy EP, Johar D, Gibson SB, Ghavami S, et al. Cancer-specific toxicity of Apoptin is independent of death receptors but involves the loss of mitochondrial membrane potential and the release of mitochondrial cell-death mediators by a Nur77-dependent pathway. J Cell Sci. 2005;118(Pt 19):4485–93.PubMedCrossRef
44.
Marsden VS, Strasser A. Control of apoptosis in the immune system: Bcl-2, BH3-only proteins and more. Annu Rev Immunol. 2003;21:71–105.PubMedCrossRef
45.
Leliveld SR, Zhang YH, Rohn JL, Noteborn MH, Abrahams JP. Apoptin induces tumor-specific apoptosis as a globular multimer. J Biol Chem. 2003;278(11):9042–51.PubMedCrossRef
46.
Leliveld SR, Dame RT, Rohn JL, Noteborn MH, Abrahams JP. Apoptin’s functional N- and C-termini independently bind DNA. FEBS Lett. 2004;557(1–3):155–8.PubMedCrossRef
47.
Danen-van Oorschot AA, Voskamp P, Seelen MC, van Miltenburg MH, Bolk MW, et al. Human death effector domain-associated factor interacts with the viral apoptosis agonist Apoptin and exerts tumor-preferential cell killing. Cell Death Differ. 2004;11(5):564–73.PubMedCrossRef
48.
Teodoro JG, Heilman DW, Parker AE, Green MR. The viral protein Apoptin associates with the anaphase-promoting complex to induce G2/M arrest and apoptosis in the absence of p53. Genes Dev. 2004;18(16):1952–7.PubMedCrossRef
49.
Huo DH, Yi LN, Yang J. Interaction with Ppil3 leads to the cytoplasmic localization of Apoptin in tumor cells. Biochem Biophys Res Commun. 2008;372(1):14–8.PubMedCrossRef
50.
Maddika S, Wiechec E, Ande SR, Poon IK, Fischer U, et al. Interaction with PI3-kinase contributes to the cytotoxic activity of Apoptin. Oncogene. 2008;27(21):3060–5.PubMedCrossRef
51.
Chen K, Luo Z, Tang J, Zheng SJ. A critical role of heat shock cognate protein 70 in Apoptin-induced phosphorylation of Akt. Biochem Biophys Res Commun. 2011;409(2):200–4.PubMedCrossRef
52.
Daugaard M, Rohde M, Jäättelä M. The heat shock protein 70 family: highly homologous proteins with overlapping and distinct functions. FEBS Lett. 2007;581(19):3702–10.PubMedCrossRef
53.
Sun GJ, Tong X, Dong Y, Mei ZZ, Sun ZX. Identification of a protein interacting with Apoptin from human leucocyte cDNA library by using yeast two-hybrid screening. Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao (Shanghai). 2002;34(3):369–72.
54.
Cheng CM, Huang SP, Chang YF, Chung WY, Yuo CY. The viral death protein Apoptin interacts with Hippi, the protein interactor of Huntingtin-interacting protein 1. Biochem Biophys Res Commun. 2003;305(2):359–64.PubMedCrossRef
55.
Guelen L, Paterson H, Gäken J, Meyers M, Farzaneh F, et al. TAT-apoptin is efficiently delivered and induces apoptosis in cancer cells. Oncogene. 2004;23(5):1153–65.PubMedCrossRef
56.
Zhong S, Salomoni P, Ronchetti S, Guo A, Ruggero D, et al. Promyelocytic leukemia protein (PML) and Daxx participate in a novel nuclear pathway for apoptosis. J Exp Med. 2000;191(4):631–40.PubMedCrossRef
57.
Sun J, Yan Y, Wang XT, Liu XW, Peng DJ, et al. PTD4-apoptin protein therapy inhibits tumor growth in vivo. Int J Cancer. 2009;124(12):2973–81.PubMedCrossRef
58.
Jiang J, Cole D, Westwood N, Macpherson L, Farzaneh F, et al. Crucial roles for protein kinase C isoforms in tumor-specific killing by Apoptin. Cancer Res. 2010;70(18):7242–52.PubMedCrossRef
Metadata
Title
Mechanisms of Apoptin-induced cell death
Authors
Suna Zhou
Mingxin Zhang
Jia Zhang
Hui Shen
Ermek Tangsakar
Jiansheng Wang
Publication date
01-12-2012
Publisher
Springer US
Published in
Medical Oncology / Issue 4/2012
Print ISSN: 1357-0560
Electronic ISSN: 1559-131X
DOI
https://doi.org/10.1007/s12032-011-0119-2

Other articles of this Issue 4/2012

Medical Oncology 4/2012 Go to the issue

Original Paper

P-cadherin expression and basal-like subtype in breast cancers

Original Paper

Identification of a 7-gene signature that predicts relapse and survival for early stage patients with cervical carcinoma

Original Paper

CCL5-28, CCL5-403, and CCR5 genetic polymorphisms and their synergic effect with alcohol and tobacco consumptions increase susceptibility to hepatocellular carcinoma

Original Paper

Low expression of IGFBP-3 predicts poor prognosis in patients with esophageal squamous cell carcinoma

Original Paper

Comparison on therapeutic effects of RFT and RCTVP regimen in the treatment of patients with indolent B-cell lymphoma in China

Original Paper

Baseline and decline of serum ADAM28 during chemotherapy of advanced non-small cell lung cancer: a probable predictive and prognostic factor
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits