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The tumor-selective viral protein apoptin effectively kills human biliary tract cancer cells

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Abstract

Biliary tract cancer, or cholangiocarcinoma, has a poor prognosis. Resection is the only curative treatment, but only a minority of patients are eligible. Chemotherapy and γ-irradiation are merely palliative, as they are unable to remove the malignancy completely. The chicken anemia virus-derived protein apoptin induces apoptosis in a wide range of human tumor cells and is not hindered by mutations inactivating p53 or by overexpression of Bcl-2, changes known to frustrate chemotherapy and radiation therapy. We examined whether apoptin kills human biliary tract cancer cells. Expression of apoptin by means of plasmids caused extensive cell death in three independent cholangiocarcinoma cell lines, CC-LP, CC-SW, and Mz-ChA-1, regardless of their oncogenic mutations, which included inactivated p16 and p53 and the disruption of the transforming growth factor β signaling pathway. In vitro delivery of apoptin by an adenoviral vector completely eradicated cholangiocarcinoma cells. Moreover, coexpression of the broad-spectrum caspase inhibitor p35 with apoptin only delayed the induced cell death. Changes in nuclear morphology still occurred early after transfection, and nuclei eventually disintegrated, suggesting that apoptin-induced cell death in these cells is not blocked by mutations in either the initiation or execution phase of apoptosis. The efficient induction of cell death by apoptin in cholangiocarcinoma cell lines makes apoptin an attractive candidate for molecular therapy of biliary tract cancer.

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Abbreviations

CMV :

Cytomegalovirus

DAPI :

2,4-Diamino-2-phenylindole

DMEM :

Dulbecco’s modified Eagle’s medium

MOI :

Multiplicity of infection

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Acknowledgements

We thank Piter Bosma (Amsterdam Medical Center) for stimulating discussions and Aart-Gerrit Jochemsen (Leiden University Medical Center) for helpful advise and for the kind donation of the vectors pOLXALuc and pXAluc.

Author information

Author notes

  1. Mathieu H. M. Noteborn

    Present address: Leiden Institute of Chemistry, P.O. Box 9502, 2300 RA, Leiden, The Netherlands

Authors and Affiliations

  1. Department of Molecular Cell Biology, Leiden University Medical Center, P.O. Box 9503, 2300 RA, Leiden, The Netherlands

    Alexandra M. Pietersen, Joost van Tongeren & Mathieu H. M. Noteborn

  2. Leadd BV, Leiden, The Netherlands

    Alexandra M. Pietersen, Saskia A. Rutjes & Mathieu H. M. Noteborn

  3. Experimental Hepatology, AMC Liver Center, Academic Medical Center, Amsterdam, The Netherlands

    Saskia A. Rutjes & John G. Wesseling

  4. Crucell Holland BV, Leiden, The Netherlands

    Ronald Vogels

Authors
  1. Alexandra M. Pietersen
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  2. Saskia A. Rutjes
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  3. Joost van Tongeren
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  4. Ronald Vogels
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  6. Mathieu H. M. Noteborn
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Corresponding author

Correspondence to Mathieu H. M. Noteborn.

Additional information

A.M. Pietersen and S.A. Rutjes contributed equally to this manuscript

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Pietersen, A.M., Rutjes, S.A., van Tongeren, J. et al. The tumor-selective viral protein apoptin effectively kills human biliary tract cancer cells. J Mol Med 82, 56–63 (2004). https://doi.org/10.1007/s00109-003-0486-z

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  • DOI: https://doi.org/10.1007/s00109-003-0486-z

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