Metabolism of estrogens : turnover differs between platinum-sensitive and -resistant high-grade serous ovarian cancer cells

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

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 IC$_{50}$ 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, there by allowing more efficient interventions.

• Language: English
• Keywords: high-grade serous ovarian cancer, steroid hormones, metabolomics, LC-HRMS, carboplatin resistance, interleukin-6
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: MF - Faculty of Medicine
• Publication status: Published
• Publication version: Version of Record
• Year: 2020
• Number of pages: 21 str.
• Numbering: Vol. 12, iss. 2, art. 279
• PID: 20.500.12556/RUL-133268
• UDC: 616-006
• ISSN on article: 2072-6694
• DOI: 10.3390/cancers12020279
• COBISS.SI-ID: 34664665
• Publication date in RUL: 19.11.2021

Record is a part of a journal

• Title: Cancers
• Shortened title: Cancers
• Publisher: MDPI
• ISSN: 2072-6694
• COBISS.SI-ID: 517914137

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.
• Licensing start date: 01.02.2020

Secondary language

• Language: Slovenian
• Keywords: serozni rak jajčnika visoke stopnje, steroidni hormoni, metabolomika