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Overexpression of TIMP-1 and Sensitivity to Topoisomerase Inhibitors in Glioblastoma Cell Lines

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Pathology & Oncology Research

Abstract

The multifunctional protein - tissue inhibitor of metalloproteinases-1 (TIMP-1) - has been associated with a poor prognosis in several types of cancers including glioblastomas. In addition, TIMP-1 has been associated with decreased response to chemotherapy, and especially the efficacy of the family of topoisomerase (TOP) inhibitors has been related to TIMP-1. As a second line treatment of glioblastomas, the vascular endothelial growth factor (VEGF) antibody bevacizumab is administered in combination with the TOP1 inhibitor irinotecan and glioblastoma cell levels of TIMP-1 could therefore potentially influence the efficacy of such treatment. In the present study, we aimed to investigate whether a high TIMP-1 expression in glioblastoma cell lines would affect the sensitivity to TOP inhibitors, and whether TIMP-1 overexpressing cells would have alterered growth and invasion. We established TIMP-1 overexpressing subclones from two human glioblastoma cell lines. TIMP-1 overexpressing U87MG cells were significantly more resistant than low TIMP-1 expressing clones and parental cells when exposed to SN-38 (TOP1 inhibitor) or epirubicin (TOP2 inhibitor). No significant differences were observed for the TIMP-1 transfected A172 cells. Implantation of both U87MG and A172 spheroids into organotypic brain slice cultures revealed a reduced growth of TIMP-1 overexpressing U87MG spheroids, however, no significant differences in invasion were observed. The present study suggests that TIMP-1 overexpression reduces the effect of TOP inhibitors in glioblastoma. TIMP-1 also appeared to reduce spheroid growth, but did not influence invasion. Whether TIMP-1 plays a role in irinotecan resistance and has a predictive potential in glioblastoma patients remains to be elucidated.

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Acknowledgements

We would like to thank technicians Helle Wohlleben and Tanja Dreehsen Højgaard for assistance with the immunohistochemistry and Vibeke Jensen for assistance with ELISA.

Funding

The work was supported by The Danish Cancer Society, Danish Cancer Research Foundation and Fonden til Laegevidenskabens Fremme.

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Authors and Affiliations

  1. Department of Pathology, Odense University Hospital, J.B. Winsloew vej 15, DK-5000, Odense, Denmark

    Charlotte Aaberg-Jessen, Mia Dahl Sørensen, Bo Halle & Bjarne Winther Kristensen

  2. Department of Nuclear Medicine, Odense University Hospital, Sdr. Boulevard 29, DK-5000, Odense, Denmark

    Charlotte Aaberg-Jessen

  3. Institute for Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Strandboulevarden 49, DK-2100, Copenhagen, Denmark

    Louise Fogh & Nils Brünner

  4. Institute of Clinical Research, University of Southern Denmark, J.B. Winsloew vej 19, DK-5000, Odense, Denmark

    Mia Dahl Sørensen & Bjarne Winther Kristensen

  5. Department of Neurosurgery, Odense University Hospital, Sdr. Boulevard 29, DK-5000, Odense, Denmark

    Bo Halle

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  1. Charlotte Aaberg-Jessen
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  2. Louise Fogh
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Correspondence to Bjarne Winther Kristensen.

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Aaberg-Jessen, C., Fogh, L., Sørensen, M.D. et al. Overexpression of TIMP-1 and Sensitivity to Topoisomerase Inhibitors in Glioblastoma Cell Lines. Pathol. Oncol. Res. 25, 59–69 (2019). https://doi.org/10.1007/s12253-017-0312-5

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