Runx regulation of sphingolipid metabolism and survival signaling.
The Runx genes (Runx1, 2, and 3) regulate cell fate in development and can operate as either oncogenes or tumor suppressors in cancer. The oncogenic potential of ectopic Runx expression has been shown in transgenic mice that develop lymphoma in potent synergy with overexpressed Myc, and in established fibroblasts that display altered morphology and increased tumorigenicity. Candidate oncogenic functions of overexpressed Runx genes include resistance to apoptosis in response to intrinsic and extrinsic stresses. In a search for gene targets responsible for this aspect of Runx phenotype, we have identified three key enzymes in sphingolipid metabolism (Sgpp1, Ugcg, and St3gal5/Siat9) as direct targets for Runx transcriptional regulation in a manner consistent with survival and apoptosis resistance. Consistent with these changes in gene expression, mass spectrometric analysis showed that ectopic Runx reduces intracellular long-chain ceramides in NIH3T3 fibroblasts and elevated extracellular sphingosine 1 phosphate. Runx expression also opposed the activation of c-Jun-NH(2)-kinase and p38(MAPK), key mediators of ceramide-induced death, and suppressed the onset of apoptosis in response to exogenous tumor necrosis factor alpha. The survival advantage conferred by ectopic Runx could be partially recapitulated by exogenous sphingosine 1 phosphate and was accompanied by reduced phosphorylation of p38(MAPK). These results reveal a novel link between transcription factor oncogenes and lipid signaling pathways involved in cancer cell survival and chemoresistance.
Kilbey
Anna
A
Molecular Oncology Laboratory, Faculty of Veterinary Medicine, Institute of Comparative Medicine, University of Glasgow, Glasgow, United Kingdom. A.Kilbey@vet.gla.ac.uk
Terry
Anne
A
Jenkins
Alma
A
Borland
Gillian
G
Zhang
Qifeng
Q
Wakelam
Michael J O
MJ
Cameron
Ewan R
ER
Neil
James C
JC
D000818:Animals; D001665:Binding Sites; D050657:Core Binding Factor alpha Subunits / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D008246:Lysophospholipids / Q000378:metabolism / Q000494:pharmacology; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D041681:NIH 3T3 Cells; D011401:Promoter Regions, Genetic; D013107:Sphingolipids / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D050657:Core Binding Factor alpha Subunits; D008246:Lysophospholipids; D013107:Sphingolipids; C060506:sphingosine 1-phosphate; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D013110:Sphingosine