{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Janneh AH"],"funding":["BLRD VA","NIDCR NIH HHS","NIA NIH HHS","NCRR NIH HHS","NIAID NIH HHS","NCI NIH HHS","NIGMS NIH HHS","NIH HHS"],"pagination":["111742"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC9791981"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["41(10)"],"pubmed_abstract":["Crosstalk between metabolic and signaling events that induce tumor metastasis remains elusive. Here, we determine how oncogenic sphingosine 1-phosphate (S1P) metabolism induces intracellular C3 complement activation to enhance migration/metastasis. We demonstrate that increased S1P metabolism activates C3 complement processing through S1P receptor 1 (S1PR1). S1P/S1PR1-activated intracellular C3b-α'<sub>2</sub> is associated with PPIL1 through glutamic acid 156 (E156) and aspartic acid 111 (D111) residues, resulting in NLRP3/inflammasome induction. Inactivation mutations of S1PR1 to prevent S1P signaling or mutations of C3b-α'<sub>2</sub> to prevent its association with PPIL1 attenuate inflammasome activation and reduce lung colonization/metastasis in mice. Also, activation of the S1PR1/C3/PPIL1/NLRP3 axis is highly associated with human metastatic melanoma tissues and patient-derived xenografts. Moreover, targeting S1PR1/C3/PPIL1/NLRP3 signaling using molecular, genetic, and pharmacologic tools prevents lung colonization/metastasis of various murine cancer cell lines using WT and C3a-receptor1 knockout (C3aR1<sup>-/-</sup>) mice. These data provide strategies for treating high-grade/metastatic tumors by targeting the S1PR1/C3/inflammasome axis."],"journal":["Cell reports"],"pubmed_title":["Crosstalk between pro-survival sphingolipid metabolism and complement signaling induces inflammasome-mediated tumor metastasis."],"pmcid":["PMC9791981"],"funding_grant_id":["P30 CA138313","P01 CA203628","T32 AI132164","R01 CA214461","R21 CA104579","T32 GM132055","R01 CA236379","R01 CA250458","C06 RR015455","IK6 BX005235","P30 GM103339","R56 AG069769","S10 OD018113","R56 AI119026","T32 DE017551","R01 DE016572","R25 GM113278"],"pubmed_authors":["Ogretmen B","Li H","Sheridan M","Lilly M","Oleinik N","Saatci O","Szulc Z","Atkinson C","Atilgan FC","Voelkel-Johnson C","Peterson YK","Mehrotra S","Nguyen H","Janneh AH","Tomlinson S","Sahin O","Marangoni E","Kassir MF","Lee HG"],"additional_accession":[]},"is_claimable":false,"name":"Crosstalk between pro-survival sphingolipid metabolism and complement signaling induces inflammasome-mediated tumor metastasis.","description":"Crosstalk between metabolic and signaling events that induce tumor metastasis remains elusive. Here, we determine how oncogenic sphingosine 1-phosphate (S1P) metabolism induces intracellular C3 complement activation to enhance migration/metastasis. We demonstrate that increased S1P metabolism activates C3 complement processing through S1P receptor 1 (S1PR1). S1P/S1PR1-activated intracellular C3b-α'<sub>2</sub> is associated with PPIL1 through glutamic acid 156 (E156) and aspartic acid 111 (D111) residues, resulting in NLRP3/inflammasome induction. Inactivation mutations of S1PR1 to prevent S1P signaling or mutations of C3b-α'<sub>2</sub> to prevent its association with PPIL1 attenuate inflammasome activation and reduce lung colonization/metastasis in mice. Also, activation of the S1PR1/C3/PPIL1/NLRP3 axis is highly associated with human metastatic melanoma tissues and patient-derived xenografts. Moreover, targeting S1PR1/C3/PPIL1/NLRP3 signaling using molecular, genetic, and pharmacologic tools prevents lung colonization/metastasis of various murine cancer cell lines using WT and C3a-receptor1 knockout (C3aR1<sup>-/-</sup>) mice. These data provide strategies for treating high-grade/metastatic tumors by targeting the S1PR1/C3/inflammasome axis.","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Dec","modification":"2026-06-01T02:21:49.781Z","creation":"2025-04-04T00:16:14.413Z"},"accession":"S-EPMC9791981","cross_references":{"pubmed":["36476873"],"doi":["10.1016/j.celrep.2022.111742"]}}