Lipid metabolic pathways as lung cancer therapeutic targets: a computational study.
Inhibitors of lipid metabolic pathways, particularly drugs targeting the mevalonate pathway, have been suggested to be valuable in enhancing the effectiveness of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and these compounds may also be effective in patients with inherent or acquired resistance to EGFR-TKIs. The present study examined gene expression profiles in lung adenocarcinoma to characterize the interaction between growth factor signals and lipid metabolic pathways at the transcriptional level. Gene expression correlation analysis showed that genes involved in the mevalonate pathway and unsaturated fatty acid synthesis were negatively correlated with the expression of EGFR, MET and other growth factor receptor genes, as well as with the expression of genes involved in cell migration and adhesion. On the other hand, the expression of genes related to cell cycle progression, DNA repair and DNA replication were positively correlated with the metabolic pathway genes mentioned above, and a significant number of such genes had promoter domains for nuclear factor Y (NFY). Genes whose expression showed a positive correlation with NFY expression and mevalonate pathway genes were found to exhibit protein-protein interactions with several 'hub' genes, including BRCA1, that have been associated with both lung cancer and cell division. These results support the idea that inhibition of lipid metabolic pathways may be valuable as an alternative therapeutic option for the treatment of lung adenocarcinoma, and suggest that NFY is a possible molecular target for such efforts.
Faculty of Information Science and Technology, Osaka Institute of Technology, Hirakata-City, Osaka, Japan. kyano@is.oit.ac.jp
Kojiro
K
Yano
D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D000077192:Adenocarcinoma of Lung; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism; D023081:CCAAT-Binding Factor / Q000235:genetics / Q000378:metabolism; D003198:Computer Simulation; D004260:DNA Repair / Q000235:genetics; D004261:DNA Replication / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics*; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D008798:Mevalonic Acid / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D059467:Transcriptome
D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D023081:CCAAT-Binding Factor; D047428:Protein Kinase Inhibitors; C402244:nuclear factor Y; C512478:EGFR protein, human; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D008798:Mevalonic Acid