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Subject | Predicate | Object |
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http://purl.uniprot.org/citations/38200582 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
http://purl.uniprot.org/citations/38200582 | http://www.w3.org/2000/01/rdf-schema#comment | "BackgroundHepatocellular carcinoma (HCC) remains a leading life-threatening health challenge worldwide, with pressing needs for novel therapeutic strategies. Sphingosine kinase 1 (SphK1), a well-established pro-cancer enzyme, is aberrantly overexpressed in a multitude of malignancies, including HCC. Our previous research has shown that genetic ablation of Sphk1 mitigates HCC progression in mice. Therefore, the development of PF-543, a highly selective SphK1 inhibitor, opens a new avenue for HCC treatment. However, the anti-cancer efficacy of PF-543 has not yet been investigated in primary cancer models in vivo, thereby limiting its further translation.MethodsBuilding upon the identification of the active form of SphK1 as a viable therapeutic target in human HCC specimens, we assessed the capacity of PF-543 in suppressing tumor progression using a diethylnitrosamine-induced mouse model of primary HCC. We further delineated its underlying mechanisms in both HCC and endothelial cells. Key findings were validated in Sphk1 knockout mice and lentiviral-mediated SphK1 knockdown cells.ResultsSphK1 activity was found to be elevated in human HCC tissues. Administration of PF-543 effectively abrogated hepatic SphK1 activity and significantly suppressed HCC progression in diethylnitrosamine-treated mice. The primary mechanism of action was through the inhibition of tumor neovascularization, as PF-543 disrupted endothelial cell angiogenesis even in a pro-angiogenic milieu. Mechanistically, PF-543 induced proteasomal degradation of the critical glycolytic enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3, thus restricting the energy supply essential for tumor angiogenesis. These effects of PF-543 could be reversed upon S1P supplementation in an S1P receptor-dependent manner.ConclusionsThis study provides the first in vivo evidence supporting the potential of PF-543 as an effective anti-HCC agent. It also uncovers previously undescribed links between the pro-cancer, pro-angiogenic and pro-glycolytic roles of the SphK1/S1P/S1P receptor axis. Importantly, unlike conventional anti-HCC drugs that target individual pro-angiogenic drivers, PF-543 impairs the PFKFB3-dictated glycolytic energy engine that fuels tumor angiogenesis, representing a novel and potentially safer therapeutic strategy for HCC."xsd:string |
http://purl.uniprot.org/citations/38200582 | http://purl.org/dc/terms/identifier | "doi:10.1186/s12967-023-04830-z"xsd:string |
http://purl.uniprot.org/citations/38200582 | http://purl.uniprot.org/core/author | "Chen J."xsd:string |
http://purl.uniprot.org/citations/38200582 | http://purl.uniprot.org/core/author | "Huang Y."xsd:string |
http://purl.uniprot.org/citations/38200582 | http://purl.uniprot.org/core/author | "Liu D."xsd:string |
http://purl.uniprot.org/citations/38200582 | http://purl.uniprot.org/core/author | "Qi Y."xsd:string |
http://purl.uniprot.org/citations/38200582 | http://purl.uniprot.org/core/author | "Su Y."xsd:string |
http://purl.uniprot.org/citations/38200582 | http://purl.uniprot.org/core/author | "Zhao M."xsd:string |
http://purl.uniprot.org/citations/38200582 | http://purl.uniprot.org/core/author | "Zhang S."xsd:string |
http://purl.uniprot.org/citations/38200582 | http://purl.uniprot.org/core/author | "Zhao Y."xsd:string |
http://purl.uniprot.org/citations/38200582 | http://purl.uniprot.org/core/author | "Jiang Y.C."xsd:string |
http://purl.uniprot.org/citations/38200582 | http://purl.uniprot.org/core/author | "Murray M."xsd:string |
http://purl.uniprot.org/citations/38200582 | http://purl.uniprot.org/core/author | "Liu K."xsd:string |
http://purl.uniprot.org/citations/38200582 | http://purl.uniprot.org/core/author | "Don A.S."xsd:string |
http://purl.uniprot.org/citations/38200582 | http://purl.uniprot.org/core/author | "Bhatnagar A."xsd:string |
http://purl.uniprot.org/citations/38200582 | http://purl.uniprot.org/core/author | "Gorrell M.D."xsd:string |
http://purl.uniprot.org/citations/38200582 | http://purl.uniprot.org/core/author | "Liu X.T."xsd:string |
http://purl.uniprot.org/citations/38200582 | http://purl.uniprot.org/core/author | "Tran C."xsd:string |
http://purl.uniprot.org/citations/38200582 | http://purl.uniprot.org/core/author | "McCaughan G.W."xsd:string |
http://purl.uniprot.org/citations/38200582 | http://purl.uniprot.org/core/author | "Vadas M.A."xsd:string |
http://purl.uniprot.org/citations/38200582 | http://purl.uniprot.org/core/author | "Han X.D."xsd:string |
http://purl.uniprot.org/citations/38200582 | http://purl.uniprot.org/core/author | "Gamble J.R."xsd:string |
http://purl.uniprot.org/citations/38200582 | http://purl.uniprot.org/core/author | "Kavurma M.M."xsd:string |
http://purl.uniprot.org/citations/38200582 | http://purl.uniprot.org/core/author | "Chung L.H."xsd:string |