Background: Fatty 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.
Methods: FASN 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.
Results: LV-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.
Conclusions: FASN was involved in glucose metabolism via down-regulation of the AKT/ERK pathway and eventually altered the malignant phenotype in lung cancer cells.
Keywords: AKT/ERK pathway; Fatty acid synthase; Glucose metabolism; NSCLC; Xenograft.