Abstract
BackgroundFatty acid synthase (FASN) is overexpressed in most human carcinomas, including non-small cell lung cancer (NSCLC), and contributes to poor prognosis. An increasing number of studies have highlighted the potential function of FASN as both a biomarker and therapeutic target for cancers. However, the underlying molecular mechanisms of FASN in glucose metabolism and the malignant biological behavior of NSCLC remain the subjects of intensive investigation.MethodsFASN expression was depleted by FASN-siRNA in A549 and NCI-H1299 cell lines to detect the function of glucose metabolism and the malignant biological behavior of NSCLC cells. Western-blot and qPCR were applied to determine the expressions of FASN, t-AKT, p-AKT, t-ERK, p-ERK, PKM2, HK2 and AZGP1. ATP and lactate were detected to determine the activation of glucose metabolism. CCK8 and transwell assays were used to detect the proliferation, invasion, and migration capacity of the two types of NSCLC cells. The xenograft mouse model was used to evaluate tumor weights after suppression of FASN.ResultsLV-FASN-siRNA and its control lentiviral vector were successfully transfected into the two types of NSCLC cells (A549 and NCI-H1299). LV-FASN siRNA significantly suppressed FASN expression in both NSCLC cell types, and expressions of p-AKT, p-ERK, PKM2, and AZGP1 were also significantly decreased. Notably, the levels of ATP and lactate were significantly decreased after transfection with LV-FASN siRNA. The proliferation of both NSCLC cell types was decreased after suppression of FASN. The invasion and migration capacity of A549, but not NCI-H1299, were inhibited following down-regulation of FASN. In vivo, inhibition of FASN caused a marked animal tumor weight loss.ConclusionsFASN was involved in glucose metabolism via down-regulation of the AKT/ERK pathway and eventually altered the malignant phenotype in lung cancer cells.
Highlights
Fatty acid synthase (FASN) is overexpressed in most human carcinomas, including non-small cell lung cancer (NSCLC), and contributes to poor prognosis
Inhibition of FASN expression by lentiviral vectors-FASNRNAi of two NSCLC cell lines To interfere with the FASN gene, A549 and NCI-H1299 cells were transfected separately with LV-FASN-siRNA to target FASN mRNA
Inhibition of FASN suppressed the migration and invasion of A549 cells, but not NCI-H1299 cells. These results suggest that FASN could be a key regulator of migration and invasion in NSCLC cells, but it is not ubiquitous in all NSCLC cells since A549 was isolated from primary lung cancer while NCI-H1299 was isolated from metastatic lung cancer and contained the NRAS gene mutant
Summary
Fatty acid synthase (FASN) is overexpressed in most human carcinomas, including non-small cell lung cancer (NSCLC), and contributes to poor prognosis. The underlying molecular mechanisms of FASN in glucose metabolism and the malignant biological behavior of NSCLC remain the subjects of intensive investigation. The enhancement of glucose metabolism in cancer cells provides sufficient ATP and numerous carbon intermediates for the biosynthesis of lipids, amino acids, and nucleotides in most human cancers [3]. A key biosynthetic enzyme of de novo fatty acid synthesis, FASN is over-expressed in most tumors and its activity is required for the malignant biological behavior of tumor cells. The relationship between FASN and glucose metabolism in NSCLC is largely unknown
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