7-Ketocholesterol induces P-glycoprotein through PI3K/mTOR signaling in hepatoma cells.

摘要: 7-Ketocholesterol (7-KC) is found at an elevated level in patients with cancer and chronic liver disease. The up-regulation of efflux pump, P-glycoprotein (P-gp) leads to drug resistance. To elucidate the effect 7-KC on P-gp, P-gp function expression were investigated hepatoma cell lines Huh-7 HepG2 primary hepatocyte-derived HuS-E/2 cells. At a subtoxic concentration, 48-h exposure reduced intracellular accumulation cytotoxicity substrate doxorubicin cells, but not In through activation phosphatidylinositol 3-kinase (PI3K)/mammalian target rapamycin (mTOR) pathway. activated downstream protein synthesis initiation factor 4E-BP1 induced post-transcriptionally. stimulation was reversible could be prevented by N-acetyl cysteine. Total cellular ATP content remained same, whereas lactate production increased fluorescence lifetime protein-bound NADH shortened. These changes suggested metabolic shift glycolysis, glycolytic inhibitors did eliminate 7-KC-mediated induction. results demonstrate that induces PI3K/mTOR signaling decreased cell-killing efficacy