The SP1-12LOX axis promotes chemoresistance and metastasis of ovarian cancer

Abstract

Background: Ovarian cancer is the most lethal gynecologic cancer. Chemoresistance, especially platinumresistance, 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. Methods: Cisplatin (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 cotranscription factor of interest genes. Tumor growth and metastasis in the liver were assessed with nude mice by subcutaneously injection of SKOV3-R cells. Results: SKOV3-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 AAmetabolism 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. Conclusion: Our 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.

Inflammation and tumor progression: signaling pathways and targeted intervention

“…For instance, low dose of LXA 4 could inhibit the proliferation and metastasis in OVC cells, Hela cells, as well as in papilloma. 350,408,409 Besides, RvD1 and RvD2 were shown to prevent metastasis of A549 by reducing EMT induced by TGF-β1. 410 Likewise, RvD1 was reported to induce caspase-3, thus increasing the apoptosis of pancreatic ductal adenocarcinoma cells in vitro.…”

Identification of key pseudogenes in nasopharyngeal carcinoma based on RNA-Seq analysis

“…Critical factors taking part in arachidonic acid metabolism regulate tumor growth and therapeutic resistance, such as Acyl-CoA synthetase 4 ( ACSL4 ) in prostate tumor [ 53 ], hypermethylated genes in esophageal squamous cell carcinoma [ 54 ], the coding gene of epoxide hydrolase 2 (EPHX2 ) in prostate cancer [ 55 ], 12-lipoxygenase ( 12LOX ) in ovarian cancer [ 56 ], etc. Thus, arachidonic acid metabolic pathway participates in the development of malignancies.…”

Mithramycin and Analogs for Overcoming Cisplatin Resistance in Ovarian Cancer

“…Sp1 has also been implicated in chemotherapy resistance [ 63 ]. In a study utilizing platinum-resistant SKOV3 cells, SP1 was upregulated and involved in the transcription of drug resistance proteins, MRP1, and MRP4 [ 63 ].…”

“…Sp1 has also been implicated in chemotherapy resistance [ 63 ]. In a study utilizing platinum-resistant SKOV3 cells, SP1 was upregulated and involved in the transcription of drug resistance proteins, MRP1, and MRP4 [ 63 ]. Increased expression of SP1 in clear cell ovarian cancer lines reduces sensitivity to SN-38, an irinotecan derivative, by upregulating the expression of Heparin-binding epidermal growth factor-like growth factor (HB-EGF) in vitro [ 64 ].…”

“…Long non-coding RNA ZFAS1 was demonstrated to be overexpressed in epithelial ovarian cancer and was associated with platinum and taxol chemoresistance via targeting a MiR-150-5p/SP1 axis [ 65 ]. In an analysis of the National Center for Biotechnology Information Gene Expression DatabaseGEO database, Sp1 was found to be overexpressed in platinum-resistant ovarian cancer patients [ 63 ]. Since Sp1-driven transcription plays an integral role in the pathogenesis of ovarian cancer and platinum-resistance mechanisms [ 38 , 42 , 66 ], and mithramycin has demonstrated a potent ability to inhibit Sp1, mithramycin or its more selective, safer analogs could be a potential strategy to overcome platinum resistance.…”