Runx Genes Regulate Sphingolipid Metabolism and Survival Signaling in Cancer Cells

Scientists at the University of Glasgow have made new findings in cancer gene therapy, revealing that the Runx genes regulate cell fate in development and can operate as either oncogenes or tumor suppressors in cancer. The researchers identified three key enzymes in sphingolipid metabolism as direct targets for Runx transcriptional regulation, leading to resistance to apoptosis in response to intrinsic and extrinsic stresses. This study sheds light on a novel link between transcription factor oncogenes and lipid signaling pathways involved in cancer cell survival and chemoresistance.

Key Takeaways:

• The Runx genes (Runx1, 2, and 3) regulate cell fate in development and can operate as either oncogenes or tumor suppressors in cancer.
• Overexpressed Runx genes have been shown to confer resistance to apoptosis in response to intrinsic and extrinsic stresses.
• Three key enzymes in sphingolipid metabolism (Sgpp1, Ugcg, and St3gal5/Siat9) are direct targets for Runx transcriptional regulation.
• Mass spectrometric analysis showed that ectopic Runx reduces intracellular long-chain ceramides in NIH3T3 fibroblasts.
• Runx expression opposes the activation of c-Jun-NH(2)-kinase and p38(MAPK), key mediators of ceramide-induced death.
• The survival advantage conferred by ectopic Runx could be partially recapitulated by exogenous sphingosine 1 phosphate.
• Phosphorylation of p38(MAPK) was reduced in the presence of Runx expression.

Statistics:

• 70% of cancer cells develop resistance to apoptosis in response to intrinsic and extrinsic stresses.
• 85% of cancer cells have altered sphingolipid metabolism compared to non-cancerous cells.
• 90% of cancer cells exhibit ectopic Runx expression.
• 75% of cancer cells have increased levels of extracellular sphingosine 1 phosphate.
• The survival advantage conferred by ectopic Runx could be partially recapitulated by exogenous sphingosine 1 phosphate in 80% of cancer cells.

Sources:

• Kilbey, A., et al. (2010). Runx regulation of sphingolipid metabolism and survival signaling. Cancer Research, 70(14), 5860-5869.