Oncotarget

Research Papers:

ADAM17 inhibition enhances platinum efficiency in ovarian cancer

Nina Hedemann _, Christoph Rogmans, Susanne Sebens, Daniela Wesch, Manuel Reichert, Dirk Schmidt-Arras, Hans-Heinrich Oberg, Ulrich Pecks, Marion van Mackelenbergh, Jörg Weimer, Norbert Arnold, Nicolai Maass and Dirk O. Bauerschlag

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Oncotarget. 2018; 9:16043-16058. https://doi.org/10.18632/oncotarget.24682

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Abstract

Nina Hedemann1, Christoph Rogmans1, Susanne Sebens2, Daniela Wesch3, Manuel Reichert4, Dirk Schmidt-Arras4, Hans-Heinrich Oberg3, Ulrich Pecks1, Marion van Mackelenbergh1, Jörg Weimer1, Norbert Arnold1, Nicolai Maass1 and Dirk O. Bauerschlag1

1Department of Gynecology and Obstetrics, Christian-Albrechts-University Kiel and University Medical Center Schleswig-Holstein Campus Kiel, Kiel, Germany

2Institute for Experimental Cancer Research, Christian-Albrechts-University Kiel and University Medical Center Schleswig-Holstein Campus Kiel, Kiel, Germany

3Institute of Immunology, Christian-Albrechts-University and University Medical Center Schleswig-Holstein Campus Kiel, Kiel, Germany

4Institute of Biochemistry, Christian-Albrechts-University Kiel, Kiel, Germany

Correspondence to:

Nina Hedemann, email: Nina.Hedemann@uksh.de

Dirk O. Bauerschlag, email: Dirk.Bauerschlag@uksh.de

Keywords: ovarian cancer; chemo resistance; ADAM17; amphiregulin; tumor therapy

Received: April 04, 2017    Accepted: February 28, 2018    Published: March 23, 2018

ABSTRACT

Chemotherapeutic resistance evolves in about 70 % of ovarian cancer patients and is a major cause of death in this tumor entity. Novel approaches to overcome these therapeutic limitations are therefore highly warranted. A disintegrin and metalloprotease 17 (ADAM17) is highly expressed in ovarian cancer and required for releasing epidermal growth factor receptor (EGFR) ligands like amphiregulin (AREG). This factor has recently been detected in ascites of advanced stage ovarian cancer patients. However, it is not well understood, whether and how ADAM17 might contribute to chemo resistance of ovarian cancer.

In this study, we identified ADAM17 as an essential upstream regulator of AREG release under chemotherapeutic treatment in ovarian cancer cell lines and patient derived cells. In the majority of ovarian cancer cells cisplatin treatment resulted in enhanced ADAM17 activity, as shown by an increased shedding of AREG. Moreover, both mRNA and the protein content of AREG were dose-dependently increased by cisplatin exposure. Consequently, cisplatin strongly induced phosphorylation of ADAM17-downstream mediators, the EGFR and extracellular signal-regulated kinases (ERK). Phorbol 12-myristate 13-acetate (PMA), similarly to cisplatin, mediated AREG shedding and membrane fading of surface ADAM17.

Inhibition of ADAM17 with either GW280264X or the anti-ADAM17 antibody D1 (A12) as well as silencing of ADAM17 by siRNA selectively reduced AREG release. Thus, ADAM17 inhibition sensitized cancer cells to cisplatin-induced apoptosis, and significantly reduced cell viability.

Based on these findings, we propose that targeting of ADAM17 in parallel to chemotherapeutic treatment suppresses survival pathways and potentially diminish evolving secondary chemo resistance mechanisms.


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