Cholesterol promoted the proliferation and metastasis of lung adenocarcinoma by regulating MYADM/c-Myc/MCT1 axis

Abstract

AbstractCholesterol disorder has been implicated in the progression of lung cancer, the mechanism of which remains largely unknown. In this study, we evidenced that cholesterol promoted the proliferation, migration and invasion of lung adenocarcinoma cells (LAC) in vitro, and enhanced LAC metastasis in vivo. Further investigation demonstrated that cholesterol treatment induced the expression of MYADM. Cholesterol-induced interaction between MYADM and Rac1 triggered AKT phosphorylation and c-Myc expression. c-Myc positively regulated the transcriptions of MCT1 and MYADM. MYADM knockdown notably inhibited the expression of Rac1, phosphorylated AKT, c-Myc and MCT1 despite in the presence of cholesterol. Blocking AKT phosphorylation restrained cholesterol-induced the expression of MYADM, Rac1 and c-Myc while AKT activation elevated the levels of MYADM, Rac1 and c-Myc. In addition, MYADM knockdown promoted E-Cadherin expression, and inhibited the expression of β-Catenin, MMP2, MMP9 and vimentin. As expected, inhibiting MYADM significantly attenuated cholesterol-induced proliferation, migration and invasion of LAC in vitro, and reduced high cholesterol diet-induced LAC metastasis in vivo. Intriguingly, MYADM knockdown remarkably decreased the levels of lactate in serum and tumors, confirming the positive regulator of MYADM in MCT1 expression. These results suggested that cholesterol should induce the proliferation and metastasis of LAC by regulating MYADM/Rac1/AKT/c-Myc/MCT1 axis.