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

Abstract：

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

journal_name

Biochem Pharmacol

journal_title

Biochemical pharmacology

authors

Wang SF,Chou YC,Mazumder N,Kao FJ,Nagy LD,Guengerich FP,Huang C,Lee HC,Lai PS,Ueng YF

doi

10.1016/j.bcp.2013.06.006

keywords:

["3-(4,5-dimethyl-thiazol-2yl)-2,5-diphenyl tetrazolium","4E-BP1","7-KC","7-Ketocholesterol","7-ketocholesterol","AKI","Akt kinase inhibitor","ERK","FBS","FLIM","GAPDH","Glycolysis","Hepatoma","LDH","MDR","MTT","NADH","P-Glycoprotein","P-glycoprotein","P-gp","PBMC","PCR","PI3K","PI3K\/mTOR","ROS","RT","Rh123","eukaryotic translation initiation factor (eIF) 4E-binding protein 1","extracellular signal-regulated kinase","fetal bovine serum","fluorescence lifetime imaging","glyceraldehyde 3-phosphate dehydrogenase","lactate dehydrogenase","mTOR","mammalian target of rapamycin","multidrug resistance","p70 ribosomal protein S6 kinase","p70S6K","peripheral blood mononuclear cells","phosphatidylinositol 3-kinase","polymerase chain reaction","reactive oxygen species","reduced nicotinamide adenine dinucleotide","reverse transcription","rhodamine 123"]

subject

Has Abstract

pub_date

2013-08-15 00:00:00

pages

548-60

issue

eissn

0006-2952

issn

1873-2968

pii

S0006-2952(13)00377-8

journal_volume

pub_type

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