ArticleMolecular cancer research : MCR2019
SPHK1 Is a Novel Target of Metformin in Ovarian Cancer.
Article in Molecular cancer research : MCR, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 73 citations in OpenAlex.
- MEOX1 Coordinates Autocrine-Paracrine Programs via SPHK1/S1P to Promote Lymph Node Metastasis in Ovarian Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Novel lipid metabolism-related gene signature associated with clinical and immune features in lung adenocarcinoma patients experiencing lymph node metastasis.Translational lung cancer research · 2026Article
- Tumor-associated macrophages and platelets in tumor microenvironment and its potential therapeutic role in ovarian cancer.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2026Review
- A Perspective on the Role of Metformin in Treating Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long COVID.ACS pharmacology & translational science · 2025Review
- Metformin Induces Changes in Sphingosine-1-Phosphate-Related Signaling in Diabetic Mice Brain.International journal of molecular sciences · 2025Article
- Machine learning models to identify lead compound and substitution optimization to have derived energetics and conformational stability through docking and MD simulations for sphingosine kinase 1.Molecular diversity · 2025Article
- Sphingolipid modulation and anti-tumor activity of Jaspine B in HepG2 bearing mice.Archives of pharmacal research · 2025Article
- SPHK1 enhances olaparib resistance in ovarian cancer through the NFκB/NRF2/ferroptosis pathway.Cell death discovery · 2025Article
- Development of a Prognostic Risk Model Based on Oxidative Stress-related Genes for Platinum-resistant Ovarian Cancer Patients.Recent patents on anti-cancer drug discovery · 2025Article
- Signaling controversy and future therapeutical perspectives of targeting sphingolipid network in cancer immune editing and resistance to tumor necrosis factor-α immunotherapy.Cell communication and signaling : CCS · 2024Review
- SPHK1 promotes HNSCC immune evasion by regulating the MMP1-PD-L1 axis.Theranostics · 2024Article
- Metformin and its potential influence on cell fate decision between apoptosis and senescence in cancer, with a special emphasis on glioblastoma.Frontiers in oncology · 2024Review
- Novel function of biguanides in inhibition of phospholipase D1 expression via a translational mechanism in cancer cells.Genes & diseases · 2023Article
- Pharmacometabolomic Approach to Investigate the Response to Metformin in Patients with Type 2 Diabetes: A Cross-Sectional Study.Biomedicines · 2023Article
- Review
- Beneficial Effects of Hordenine on a Model of Ulcerative Colitis.Molecules (Basel, Switzerland) · 2023Article
- HOXC11 drives lung adenocarcinoma progression through transcriptional regulation of SPHK1.Cell death & disease · 2023Article
- Sphingosine Kinase-1 (SPHK1) promotes inflammation in infantile pneumonia by regulating NLRP3 inflammasome and SIRT1 expression.Histology and histopathology · 2022Article
- Metabolic Reprogramming in Tumor-Associated Macrophages in the Ovarian Tumor Microenvironment.Cancers · 2022Review
- Targeting SPHK1/PBX1 Axis Induced Cell Cycle Arrest in Non-Small Cell Lung Cancer.International journal of molecular sciences · 2022Article
Corrections and comments
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Authors and funding
12 authors at 4 institutions in 2 countries.
Funding
Abstract
The role of phospholipid signaling in ovarian cancer is poorly understood. Sphingosine-1-phosphate (S1P) is a bioactive metabolite of sphingosine that has been associated with tumor progression through enhanced cell proliferation and motility. Similarly, sphingosine kinases (SPHK), which catalyze the formation of S1P and thus regulate the sphingolipid rheostat, have been reported to promote tumor growth in a variety of cancers. The findings reported here show that exogenous S1P or overexpression of SPHK1 increased proliferation, migration, invasion, and stem-like phenotypes in ovarian cancer cell lines. Likewise, overexpression of SPHK1 markedly enhanced tumor growth in a xenograft model of ovarian cancer, which was associated with elevation of key markers of proliferation and stemness. The diabetes drug, metformin, has been shown to have anticancer effects. Here, we found that ovarian cancer patients taking metformin had significantly reduced serum S1P levels, a finding that was recapitulated when ovarian cancer cells were treated with metformin and analyzed by lipidomics. These findings suggested that in cancer the sphingolipid rheostat may be a novel metabolic target of metformin. In support of this, metformin blocked hypoxia-induced SPHK1, which was associated with inhibited nuclear translocation and transcriptional activity of hypoxia-inducible factors (HIF1α and HIF2α). Further, ovarian cancer cells with high SPHK1 were found to be highly sensitive to the cytotoxic effects of metformin, whereas ovarian cancer cells with low SPHK1 were resistant. Together, the findings reported here show that hypoxia-induced SPHK1 expression and downstream S1P signaling promote ovarian cancer progression and that tumors with high expression of SPHK1 or S1P levels might have increased sensitivity to the cytotoxic effects of metformin. IMPLICATIONS: Metformin targets sphingolipid metabolism through inhibiting SPHK1, thereby impeding ovarian cancer cell migration, proliferation, and self-renewal.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.