Possible role of estrogen metabolism and aldo-keto reductase activity in chemoresistance of ovarian cancer

Abstract

High-grade serous ovarian cancer (HGSOC) is the most aggressive and chemoresistant form of epithelial ovarian cancer (OC) and is responsible for ~80% of OC-related deaths. OC is associated with disturbed estrogen action. In postmenopausal patients, estrogens are formed locally from steroid precursors. Enzymes of the AKR1C subfamily are associated with resistance to chemotherapeutic agents and are involved in the biosynthesis and metabolism of steroid hormones, thus may contribute to the growth of hormone-dependent tumors. To date, the interplay of estrogen synthesis and aldo-keto reductase activity in HGSOC chemoresistance remains unclear. The aim of this study was to investigate the differences in targeted transcriptomics of HGSOC cell lines with different sensitivity to carboplatin: OVSAHO, OVCAR-3, Kuramochi, OVCAR-4, Caov- 3, and COV362, and to evaluate the differences in correlation patterns between targeted gene expression profiles in platinum-sensitive and -resistant patients using publicly available data (PAD) (cBioPortal). We first determined the expression of genes involved in estrogen biosynthesis/metabolism (STS, SULT1E1, HSD17B1, HSD17B2, HSD17B14, PAPSS1, PAPSS2), steroid transport (SLCO1A2, SLCO1B3, SLCO2B1, SLCO4A1, SLCO4C1, ABCC1, ABCC4, ABCC11, ABCG2, SLC51A, SLC51B), estrogen action (ESR1, ESR2, GPER) and oxidative metabolism (CYP1A1, CYP1A2, CYP1B1, SULT1A1, SULT2B1, SULT1E1, UGTB7, COMT, NOQ1, NOQ2, GSTP1), NFE2L2 and AKR1C1-3 by qPCR. Next, by using PAD we conducted a correlation analysis using the Pearson correlation coefficient for gene expression data of targeted genes in OC patients. The patients were classified into two groups based on their response to platinum treatment: sensitive and resistant. The correlation matrix was computed independently for each group. Expression analysis revealed that the estrogen receptor ESR2, the efflux transporter ABCG2 and aldo-keto reductase AKR1C1 were highly expressed in the most resistant cell lines COV362 and Caov-3. The mRNA levels of estrogen biosynthesis and oxidative metabolism genes STS, HSD17B14, NOQ1, and GSTP1 increased with carboplatin resistance in the HGSOC cell lines. These results indicate the potential of ESR2, STS, HSD17B14, NOQ1, GSTP1, and ABCG2 as predictive markers for HGSOC chemoresistance. Furthermore, analysis of PAD revealed different correlation profiles between genes in sensitive and resistant patients. In chemoresistant were found a moderately to strong positive correlations (p<0.001) between gene pairs including AKR1C1– AKR1C3, AKR1C1 – NFE2L2, AKR1C1 – SULT1E1, NOQ1 – HSD17B14, COMT – SULT1A1, ABCG2 – SLC515. In chemosensitive patients was found a strong positive correlation (p<0.001) between gene pair CYP1B1 – SULT1E1. The correlation differences between sensitive and resistant OC patients suggest possible gene regulatory networks or molecular interactions contributing to the heterogeneity of response to platinum in OC. Further studies are ongoing to elucidate the mechanism of the interplay between local estrogen metabolism and aldo-keto reductase activity in HGSOC chemoresistance