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

Wang SF, Chou YC, Mazumder N, Kao FJ, Nagy LD, Guengerich FP, Huang C, Lee HC, Lai PS, Ueng YF
Biochem Pharmacol. 2013 86 (4): 548-60

PMID: 23792120 · PMCID: PMC4164904 · DOI:10.1016/j.bcp.2013.06.006

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.

Copyright © 2013 Elsevier Inc. All rights reserved.

MeSH Terms (22)

Acetylcysteine Antibiotics, Antineoplastic Antioxidants ATP Binding Cassette Transporter, Subfamily B, Member 1 Carcinoma, Hepatocellular Cell Line Cell Line, Tumor Cell Survival Cholesterol Doxorubicin Drug Resistance, Neoplasm Hepatocytes Humans Hydroxycholesterols Ketocholesterols Lactic Acid Oligomycins Phosphatidylinositol 3-Kinases Phosphoinositide-3 Kinase Inhibitors Signal Transduction TOR Serine-Threonine Kinases Up-Regulation

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