Lipid metabolic pathways as lung cancer therapeutic targets: A computational study

Abstract

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.

Inferences of individual drug responses across diverse cancer types using a novel competing endogenous RNA network

“…The result showed that six drugs (vorinostat, celecoxib, lapatinib, vinorelbine, clofarabine, and simvastatin) with PCCs ≥0.4 with about 50% or more DRCEs, in which the first four drugs have been used to treat lung cancer (Altorki et al ., 2003; Fossella et al ., 2000; Ramalingam et al ., 2010; Ross et al ., 2010). Simvastatin is a lipid‐lowering drug, and previous study has indicated that lipid metabolic pathways may be valuable as lung cancer therapeutic targets (Yano, 2012). The chemical structure of simvastatin is highly similar to that of five of seven drugs (Fig.…”

Screening of feature genes of the ovarian cancer epithelia with DNA microarray

“…These lipids regulate a variety of cellular functions including cell proliferation, survival and migration by either activating other signaling proteins inside the cells, or binding to a series of G protein-coupled receptors (GPCRs) on the cell surfaces. It has been reported that 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) [33]. On the other hand, oncogenic signaling pathways can regulate lipid metabolism at multiple steps, including transcriptional, translational and post-translational levels.…”

Viewing cancer pathophysiology as a lead in understanding cardiac and vascular disease mechanisms

“…My proposition is that prenylation -a post-translational modification -is central in cardioprotection and protein targets are predicted and indeed, defined, through examining cancer. Such cancer prosurvival lipid metabolic pathway mechanisms [8] are closely paralleled in the heart. Notably, consistent with this proposition, by inhibiting lipid metabolic paths, particularly the mevalonate pathway, anti-cancer therapeutics are enhanced [8].…”

“…Such cancer prosurvival lipid metabolic pathway mechanisms [8] are closely paralleled in the heart. Notably, consistent with this proposition, by inhibiting lipid metabolic paths, particularly the mevalonate pathway, anti-cancer therapeutics are enhanced [8]. Further, in cancer, prosurvival prenylation reactions have been earlier considered to be suited targets for therapies [9].…”

“…Therefore this understanding has clear clinical implications in regards appreciating and indeed foretelling cardioprotection against I/R injury. Prenylation (the addition of hydrophobic moiety to a protein to assist in cell membrane attachment) is a cancer prosurvival mechanism [8,9] and is a suggested mechanism that may lead also to ischaemic cardioprotection [1] with farnesol being an active component of this process.…”