Abstract
BackgroundOvarian cancer is the most lethal gynecologic cancer. Chemoresistance, especially platinum-resistance, is closely related to metastasis of ovarian cancer, however, the molecular basis by which links chemoresistance and metastasis remains vague. Disordered arachidonic acid (AA) metabolism has been shown to play an important role in the advanced ovarian cancer. This study aimed to explore the underlying mechanism involving eicosanoid metabolism that controlling chemoresistance and metastasis of ovarian cancer.MethodsCisplatin (DDP)-resistant SKOV3 (SKOV3-R) cells were constantly induced. Ultra-high-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was performed to determine the AA metabolism in SKOV3 and SKOV3-R cells. Half maximal inhibitory concentration (IC50) and percentage of cell viability were tested using cell counting kit 8 (CCK-8). Realtime quantitative PCR (qPCR) and immunohistochemistry (IHC) were used to evaluate indicated genes and proteins respectively. Bioinformatic analysis and chromatin immunoprecipitation (ChIP) were performed to predict and identify the co-transcription factor of interest genes. Tumor growth and metastasis in the liver were assessed with nude mice by subcutaneously injection of SKOV3-R cells.ResultsSKOV3-R cells expressed higher multidrug resistance-associated proteins (MRPs) MRP1 and MRP4. They showed enhanced metastatic ability and produced increased AA-derived eicosanoids. Mechanistically, MRPs, epithelial mesenchymal transition (EMT) markers Snail and Slug, as well as key enzymes involved in AA-metabolism including 12-lipoxygenase (12LOX) were transcribed by the mutual transcription factor SP1 which was consistently upregulated in SKOV3-R cells. Inhibition of SP1 or 12LOX sensitized SKOV3-R cells to DDP and impaired metastasis in vitro and in vivo.ConclusionOur results reveal that SP1-12LOX axis signaling plays a key role in DDP-resistance and metastasis, which provide a new therapeutic target for ovarian cancer.
Highlights
The lethality of ovarian cancer ranks the first in gynecologic cancers, and the majority of patients with ovarian cancer are diagnosed at the advanced stage at their first clinical evaluation (Torre et al 2018)
We found that the promoters of MRP1 (ABCC1), MRP4 (ABCC4), Slug, Snail, cytochrome P450 2 J2 (CYP2J2), 12LOX (ALOX12), and cyclooxygenase 1 (COX1) (PTGS1) shared a mutual transcription factor Sp1 transcription factor (SP1) (Fig. 2a and b)
The The Cancer Genome Atlas (TCGA) database analysis showed that SP1 expression negatively correlated with survival in ovarian cancer patients (Fig. 2g). These results indicate that SP1 is the mutual transcription factor of MRP1, MRP4, Snail, Slug, COX1, 12LOX, and CYP2J2, which links platinum-resistance, metastasis, and arachidonic acid (AA) metabolism in ovarian cancer
Summary
The lethality of ovarian cancer ranks the first in gynecologic cancers, and the majority of patients with ovarian cancer are diagnosed at the advanced stage at their first clinical evaluation (Torre et al 2018). The regular therapy for ovarian cancer is cytoreductive surgery plus platinum-based chemotherapy (Ledermann et al 2018). Uncovering the mechanisms of platinum-resistance and metastasis is crucial for developing effective treatments to improve the prognosis of patients with ovarian cancer. The multidrug resistance-related proteins (MRPs) are well-known associated with chemoresistance of ovarian cancer (Surowiak et al 2006). Disordered AA metabolism was confirmed to play an important role in the advanced ovarian cancer (Freedman et al 2007). The underlying mechanisms linking chemoresistance to metastasis and whether AA metabolites contribute to this linkage are not yet clear. Disordered arachidonic acid (AA) metabolism has been shown to play an important role in the advanced ovarian cancer. This study aimed to explore the underlying mechanism involving eicosanoid metabolism that controlling chemoresistance and metastasis of ovarian cancer
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