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

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.

Recent Metabolomics Analysis in Tumor Metabolism Reprogramming

“…Metabolomics can be used to distinguish between platinum resistance and metabolite levels. Poschner et al used LC-MS to characterize the levels of steroids, active estrogen, and sulfated or aldehyde glucose during the development of platinum resistance in ovarian cancer and found that these metabolites are highly expressed in carboplatin-sensitive cells (Poschner et al, 2020). In a study of non-small cell lung cancer (NSCLC), cisplatin-resistant cells were more sensitive to nutrient deprivation than were sensitive cells, and adding glutamine to cisplatin-resistant cells restored cell death due to nutrient deprivation by increasing the intracellular nucleotide concentration.…”

Model Cell Lines and Tissues of Different HGSOC Subtypes Differ in Local Estrogen Biosynthesis

“…We examined the expression (Cq < 35) of 50 genes: 13 uptake and five efflux transporters of steroid precursors, 16 biosynthetic, and 13 metabolic enzymes for estrogens, two nuclear receptors, and all three variants of the membrane estrogen receptor ( Figure 1 ). We used the normal ovarian epithelial cell line HIO-80 and three different chemoresistant HGSOC cell lines: the least chemoresistant OVSAHO (cisplatin IC50~3.7 µM [ 25 ], carboplatin IC50 = 9.4 µM [ 37 ]), moderately chemoresistant Kuramochi (cisplatin IC50~10.4 µM [ 25 ], carboplatin IC50 = 12 µM [ 37 ]), and highly chemoresistant COV362 cell line (cisplatin IC50 = 13.57 µM [ 25 ], carboplatin IC50 = 318.2 µM [ 38 ]).…”

“…Estrogens most likely play a more important role in OVSAHO cells because these cells are responsive to estradiol when grown as 3D spheroids, whereas COV362 cells are not [ 39 ]. Additionally, OVSAHO cells are the least chemoresistant of the evaluated cells, and studies have shown that carboplatin-sensitive cells produce more steroid hormones and metabolites than platinum-resistant cells [ 37 ]. Nevertheless, the lack of E1-S metabolism cannot exclude the possibility of the paracrine or endocrine roles of estrogens in the COV362 cells, considering that ESR1 expression at the mRNA level is relatively high, and ERα expression at the protein level is moderate (compared to the OVSAHO and Kuramochi cells) [ 39 ].…”

Metabonomic analysis of tumor microenvironments: a mini-review

“…The metabolic patterns of cancer cells change after the development of drug resistance. The same drug can induce different metabolic changes in sensitive and drug-resistant cells (47). Thus, metabolomics can be used to detect metabolic changes in cells and their response to drugs to determine whether tumor cells are resistant to drugs, and to monitor drug resistance at an early stage.…”