Metabolism of Estrogens: Turnover Differs between Platinum-Sensitive and -Resistant High-Grade Serous Ovarian Cancer Cells
by
Stefan Poschner 1, Judith Wackerlig 2, Dan Cacsire Castillo-Tong 3, Andrea Wolf 3, Isabel von der Decken 3, Tea Lanišnik Rižner 4, Renata Pavlič 4
, Anastasia Meshcheryakova 5, Diana Mechtcheriakova 5, Monika Fritzer-Szekeres 6, Theresia Thalhammer 5 and Walter Jäger 1,7,*
Stefan Poschner 1, Judith Wackerlig 2, Dan Cacsire Castillo-Tong 3, Andrea Wolf 3, Isabel von der Decken 3, Tea Lanišnik Rižner 4, Renata Pavlič 4, Anastasia Meshcheryakova 5, Diana Mechtcheriakova 5, Monika Fritzer-Szekeres 6, Theresia Thalhammer 5 and Walter Jäger 1,7,*
1
Division of Clinical Pharmacy and Diagnostics, Department of Pharmaceutical Chemistry, University of Vienna, 1090 Vienna, Austria
2
Division of Drug Design and Medicinal Chemistry, Department of Pharmaceutical Chemistry, University of Vienna, 1090 Vienna, Austria
3
Translational Gynecology Group, Department of Obstetrics and Gynecology, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria
4
Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
5
Department of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, 1090 Vienna, Austria
6
Department of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, 1090 Vienna, Austria
7
Vienna Metabolomics Center (VIME), University of Vienna, 1090 Vienna, Austria
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(2), 279; https://doi.org/10.3390/cancers12020279
Received: 9 December 2019 / Revised: 9 January 2020 / Accepted: 21 January 2020 / Published: 23 January 2020
(This article belongs to the Special Issue Preclinical and Clinical Advances in Ovarian Cancer)
High-grade serous ovarian cancer (HGSOC) is currently treated with cytoreductive surgery and platinum-based chemotherapy. The majority of patients show a primary response; however, many rapidly develop drug resistance. Antiestrogens have been studied as low toxic treatment options for HGSOC, with higher response rates in platinum-sensitive cases. Mechanisms for this difference in response remain unknown. Therefore, the present study investigated the impact of platinum resistance on steroid metabolism in six established HGSOC cell lines sensitive and resistant against carboplatin using a high-resolution mass spectrometry assay to simultaneously quantify the ten main steroids of the estrogenic metabolic pathway. An up to 60-fold higher formation of steroid hormones and their sulfated or glucuronidated metabolites was observed in carboplatin-sensitive cells, which was reversible by treatment with interleukin-6 (IL-6). Conversely, treatment of carboplatin-resistant cells expressing high levels of endogenous IL-6 with the monoclonal anti-IL-6R antibody tocilizumab changed their status to “platinum-sensitive”, exhibiting a decreased IC50 value for carboplatin, decreased growth, and significantly higher estrogen metabolism. Analysis of these metabolic differences could help to detect platinum resistance in HGSOC patients earlier, thereby allowing more efficient interventions.
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Keywords:
high-grade serous ovarian cancer; steroid hormones; metabolomics; LC-HRMS; carboplatin resistance; interleukin-6
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MDPI and ACS Style
Poschner, S.; Wackerlig, J.; Castillo-Tong, D.C.; Wolf, A.; von der Decken, I.; Rižner, T.L.; Pavlič, R.; Meshcheryakova, A.; Mechtcheriakova, D.; Fritzer-Szekeres, M.; Thalhammer, T.; Jäger, W. Metabolism of Estrogens: Turnover Differs between Platinum-Sensitive and -Resistant High-Grade Serous Ovarian Cancer Cells. Cancers 2020, 12, 279.
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