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

• Main Authors: 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
• Format: Article
• Language: English
• Published: MDPI AG 2020-01-01
• Series: Cancers
• Subjects: high-grade serous ovarian cancer; steroid hormones; metabolomics; lc-hrms; carboplatin resistance; interleukin-6
• Online Access: https://www.mdpi.com/2072-6694/12/2/279

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.