PMID- 29662625
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20191120
IS  - 1949-2553 (Electronic)
IS  - 1949-2553 (Linking)
VI  - 9
IP  - 22
DP  - 2018 Mar 23
TI  - ADAM17 inhibition enhances platinum efficiency in ovarian cancer.
PG  - 16043-16058
LID - 10.18632/oncotarget.24682 [doi]
AB  - 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.
FAU - Hedemann, Nina
AU  - Hedemann N
AD  - Department of Gynecology and Obstetrics, Christian-Albrechts-University Kiel and 
      University Medical Center Schleswig-Holstein Campus Kiel, Kiel, Germany.
FAU - Rogmans, Christoph
AU  - Rogmans C
AD  - Department of Gynecology and Obstetrics, Christian-Albrechts-University Kiel and 
      University Medical Center Schleswig-Holstein Campus Kiel, Kiel, Germany.
FAU - Sebens, Susanne
AU  - Sebens S
AD  - Institute for Experimental Cancer Research, Christian-Albrechts-University Kiel 
      and University Medical Center Schleswig-Holstein Campus Kiel, Kiel, Germany.
FAU - Wesch, Daniela
AU  - Wesch D
AD  - Institute of Immunology, Christian-Albrechts-University and University Medical 
      Center Schleswig-Holstein Campus Kiel, Kiel, Germany.
FAU - Reichert, Manuel
AU  - Reichert M
AD  - Institute of Biochemistry, Christian-Albrechts-University Kiel, Kiel, Germany.
FAU - Schmidt-Arras, Dirk
AU  - Schmidt-Arras D
AD  - Institute of Biochemistry, Christian-Albrechts-University Kiel, Kiel, Germany.
FAU - Oberg, Hans-Heinrich
AU  - Oberg HH
AD  - Institute of Immunology, Christian-Albrechts-University and University Medical 
      Center Schleswig-Holstein Campus Kiel, Kiel, Germany.
FAU - Pecks, Ulrich
AU  - Pecks U
AD  - Department of Gynecology and Obstetrics, Christian-Albrechts-University Kiel and 
      University Medical Center Schleswig-Holstein Campus Kiel, Kiel, Germany.
FAU - van Mackelenbergh, Marion
AU  - van Mackelenbergh M
AD  - Department of Gynecology and Obstetrics, Christian-Albrechts-University Kiel and 
      University Medical Center Schleswig-Holstein Campus Kiel, Kiel, Germany.
FAU - Weimer, Jorg
AU  - Weimer J
AD  - Department of Gynecology and Obstetrics, Christian-Albrechts-University Kiel and 
      University Medical Center Schleswig-Holstein Campus Kiel, Kiel, Germany.
FAU - Arnold, Norbert
AU  - Arnold N
AD  - Department of Gynecology and Obstetrics, Christian-Albrechts-University Kiel and 
      University Medical Center Schleswig-Holstein Campus Kiel, Kiel, Germany.
FAU - Maass, Nicolai
AU  - Maass N
AD  - Department of Gynecology and Obstetrics, Christian-Albrechts-University Kiel and 
      University Medical Center Schleswig-Holstein Campus Kiel, Kiel, Germany.
FAU - Bauerschlag, Dirk O
AU  - Bauerschlag DO
AD  - Department of Gynecology and Obstetrics, Christian-Albrechts-University Kiel and 
      University Medical Center Schleswig-Holstein Campus Kiel, Kiel, Germany.
LA  - eng
PT  - Journal Article
DEP - 20180323
PL  - United States
TA  - Oncotarget
JT  - Oncotarget
JID - 101532965
PMC - PMC5882316
OTO - NOTNLM
OT  - ADAM17
OT  - amphiregulin
OT  - chemo resistance
OT  - ovarian cancer
OT  - tumor therapy
COIS- CONFLICTS OF INTEREST The authors declare no conflict of interest.
EDAT- 2018/04/18 06:00
MHDA- 2018/04/18 06:01
PMCR- 2018/03/23
CRDT- 2018/04/18 06:00
PHST- 2017/04/04 00:00 [received]
PHST- 2018/02/28 00:00 [accepted]
PHST- 2018/04/18 06:00 [entrez]
PHST- 2018/04/18 06:00 [pubmed]
PHST- 2018/04/18 06:01 [medline]
PHST- 2018/03/23 00:00 [pmc-release]
AID - 24682 [pii]
AID - 10.18632/oncotarget.24682 [doi]
PST - epublish
SO  - Oncotarget. 2018 Mar 23;9(22):16043-16058. doi: 10.18632/oncotarget.24682. 
      eCollection 2018 Mar 23.