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

Sheng Fan Wang, Yueh Ching Chou, Nirmal Mazumder, Fu Jen Kao, Eslie D. Nagy, Peter Guengerich, Cheng Huang, Hsin Chen Lee, Ping Shan Lai, Yune Fang Ueng

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37 Scopus citations


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 posttranscriptionally. 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.

Original languageEnglish (US)
Pages (from-to)548-560
Number of pages13
JournalBiochemical Pharmacology
Issue number4
StatePublished - 2013
Externally publishedYes

Bibliographical note

Funding Information:
This study was supported mainly by grants V99C1-207 and V101C1-205 from Taipei Veterans General Hospital, Taipei and partly by an institutional grant from the National Research Institute of Chinese Medicine, Taipei . Quantification of sterols was supported by a grant R37 CA090426 from National Institute of Health, USA.


  • 7-Ketocholesterol
  • Glycolysis
  • Hepatoma
  • P-Glycoprotein
  • PI3K/mTOR


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