Runx regulation of sphingolipid metabolism and survival signaling

Kilbey, A., Terry, A., Jenkins, A., Borland, G., Zhang, Q.F., Wakelam, M.J.O., Cameron, E.R. and Neil, J.C. (2010) Runx regulation of sphingolipid metabolism and survival signaling. Cancer Research, 70(14), pp. 5860-5869. (doi: 10.1158/0008-5472.CAN-10-0726)

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Abstract

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-NH2-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. Cancer Res; 70(14); 5860-9.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Cameron, Professor Ewan and Neil, Professor James and Mcdonald, Mrs Alma and Kilbey, Dr Anna and Borland, Dr Gillian and Terry, Mrs Anne
Authors: Kilbey, A., Terry, A., Jenkins, A., Borland, G., Zhang, Q.F., Wakelam, M.J.O., Cameron, E.R., and Neil, J.C.
College/School:College of Medical Veterinary and Life Sciences > School of Veterinary Medicine
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Cancer Research
ISSN:0008-5472
ISSN (Online):1538-7445
Published Online:29 June 2010

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