Metabolism of Estrogens: Turnover Differs between Platinum-Sensitive and -Resistant High-Grade Serous Ovarian Cancer Cells

Stefan Poschner; Judith Wackerlig; Dan Cacsire Castillo-Tong; Andrea Wolf; Isabel von der Decken; Tea Lanišnik Rižner; Renata Pavlič; Anastasia Meshcheryakova; Diana Mechtcheriakova; Monika Fritzer-Szekeres; Theresia Thalhammer; Walter Jäger

doi:10.3390/cancers12020279

Titel

Metabolism of Estrogens: Turnover Differs between Platinum-Sensitive and -Resistant High-Grade Serous Ovarian Cancer Cells

Autor*in

Stefan Poschner

Department für Pharmazeutische Chemie, Fakultät für Lebenswissenschaften, Universität Wien

Judith Wackerlig

Department für Pharmazeutische Chemie, Fakultät für Lebenswissenschaften, Universität Wien

Dan Cacsire Castillo-Tong

Translational Gynecology Group, Department of Obstetrics and Gynecology, Comprehensive Cancer Center, Medical University of Vienna

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Abstract

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.

Stichwort

high-grade serous ovarian cancersteroid hormonesmetabolomicsLC-HRMScarboplatin resistanceinterleukin-6

Objekt-Typ

journal article

Sprache

Englisch [eng]

Persistent identifier

phaidra.univie.ac.at/o:1246374

DOI

10.3390/cancers12020279

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