ADAM17 inhibition enhances platinum efficiency in ovarian cancer
| Autor: | Dirk Schmidt-Arras, Christoph Rogmans, Nina Hedemann, Susanne Sebens, Jörg Weimer, Ulrich Pecks, Nicolai Maass, Marion van Mackelenbergh, Hans-Heinrich Oberg, Daniela Wesch, Dirk Bauerschlag, Norbert Arnold, Manuel Reichert |
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| Rok vydání: | 2018 |
| Předmět: |
chemo resistance
0301 basic medicine MAPK/ERK pathway 03 medical and health sciences Amphiregulin medicine Epidermal growth factor receptor Cisplatin ADAM17 biology Kinase business.industry medicine.disease ovarian cancer 030104 developmental biology Oncology Apoptosis Cancer cell Cancer research biology.protein amphiregulin tumor therapy Ovarian cancer business Research Paper medicine.drug |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| DOI: | 10.18632/oncotarget.24682 |
| Popis: | // Nina Hedemann 1 , Christoph Rogmans 1 , Susanne Sebens 2 , Daniela Wesch 3 , Manuel Reichert 4 , Dirk Schmidt-Arras 4 , Hans-Heinrich Oberg 3 , Ulrich Pecks 1 , Marion van Mackelenbergh 1 , Jorg Weimer 1 , Norbert Arnold 1 , Nicolai Maass 1 and Dirk O. Bauerschlag 1 1 Department of Gynecology and Obstetrics, Christian-Albrechts-University Kiel and University Medical Center Schleswig-Holstein Campus Kiel, Kiel, Germany 2 Institute for Experimental Cancer Research, Christian-Albrechts-University Kiel and University Medical Center Schleswig-Holstein Campus Kiel, Kiel, Germany 3 Institute of Immunology, Christian-Albrechts-University and University Medical Center Schleswig-Holstein Campus Kiel, Kiel, Germany 4 Institute 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. |
| Databáze: | OpenAIRE |
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