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

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

doi:10.1016/j.bcp.2013.06.006

Cited by 46 publications

(46 citation statements)

References 43 publications

(59 reference statements)

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“…39), which is encoded by MDR1 . Arceci and colleagues reported that rapamycin can reverse the MDR phenotype in human T-cell lymphoblastic leukemia cell lines (47), and increased activation of the PI3K/mTOR pathway was recently associated with overexpression of MDR1 in HCC (48). However, the effect of mTORC2 inhibition on MDR1 expression remained unknown.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of mTORC2 Induces Cell-Cycle Arrest and Enhances the Cytotoxicity of Doxorubicin by Suppressing MDR1 Expression in HCC Cells

Chen

Liang

et al. 2015

Molecular Cancer Therapeutics

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mTOR is aberrantly activated in hepatocellular carcinoma (HCC) and plays pivotal roles in tumorigenesis and chemoresistance. Rapamycin has been reported to exert antitumor activity in HCC and sensitizes HCC cells to cytotoxic agents. However, due to feedback activation of AKT after mTOR complex 1 (mTORC1) inhibition, simultaneous targeting of mTORC1/2 may be more effective. In this study, we examined the interaction between the dual mTORC1/2 inhibitor OSI-027 and doxorubicin in vitro and in vivo. OSI-027 was found to reduce phosphorylation of both mTORC1 and mTORC2 substrates, including 4E-BP1, p70S6K, and AKT (Ser473), and inhibit HCC cell proliferation. Similar to OSI-027 treatment, knockdown of mTORC2 induced G0–G1 phase cell-cycle arrest. In contrast, rapamycin or knockdown of mTORC1 increased phosphorylation of AKT (Ser473), yet had little antiproliferative effect. Notably, OSI-027 synergized with doxorubicin for the antiproliferative efficacy in a manner dependent of MDR1 expression in HCC cells. The synergistic antitumor effect of OSI-027 and doxorubicin was also observed in a HCC xenograft mouse model. Moreover, AKT was required for OSI-027–induced cell-cycle arrest and downregulation of MDR1. Our findings provide a rationale for dual mTORC1/mTORC2 inhibitors, such as OSI-027, as monotherapy or in combination with cytotoxic agents to treat HCC.

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Section: Discussionmentioning

confidence: 99%

Inhibition of mTORC2 Induces Cell-Cycle Arrest and Enhances the Cytotoxicity of Doxorubicin by Suppressing MDR1 Expression in HCC Cells

Chen

Liang

et al. 2015

Molecular Cancer Therapeutics

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“…Indeed, schweinfurthin G treatment‐promoted mislocalization of mTOR reduces the interaction between mTOR and its activator, RheB (Bao et al, ). In hepatocellular carcinoma cells, activity of the drug resistance export protein P‐glycoprotein (Pgp) can be induced by the oxysterol 7‐ketocholesterol in an mTOR dependent manner (Wang et al, ). However, schweinfurthin treatment reduces the activity of Pgp suggesting a potential nexus between schweinfurthin treatment, cholesterol homeostasis, and oxysterol signaling through mTOR (Sheehy et al, ).…”

Section: Mechanismmentioning

confidence: 99%

Schweinfurthins: Lipid Modulators with Promising Anticancer Activity

Koubek

Weissenrieder

Neighbors

et al. 2018

Lipids

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The schweinfurthin family of compounds displays exciting potent and differential cytotoxicity against human cancer cell lines. Currently, the effect of schweinfurthins on tumor development and progression is being explored in animal models of cancer with promising results. The first schweinfurthin family member, vedelianin, was isolated in 1992, followed by other schweinfurthins in 1998. This opened up the door for the synthesis of additional analogs. At present, the focus of research lies on delineating the mechanism of schweinfurthin action and identifying the nature of sensitivity. It appears that many of the intracellular effects of schweinfurthins are due to, or impacted by, the effect of schweinfurthins on lipid metabolism, synthesis, and homeostasis. These effects include impaired trafficking from the trans-golgi network, disruption of lipid rafts, changes in oxysterol-binding protein activity, and interference with the isoprenoid biosynthesis pathway (IBP). Cancer cells are known to rely heavily on fatty acid, lipid, and sterol synthesis for growth and proliferation. Therefore, compounds that target these needs, such as schweinfurthins, display promise as novel therapeutics. This timely review will take an in-depth look at the history of schweinfurthins, their synthesis, where the research presently stands, and the questions that remain.

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“…However, for troleandomycin, HuH-7 cells yielded a 2-fold lower k inact and 70-fold higher K I value compared to human recombinant CYP3A4 inhibition assay. A higher K I value in HuH-7 cells could be attributable to slow diffusion into the cells or active removal from the cells by export pumps (Wang et al 2013, Zhang et al 2012). A comparison between HuH-7 cells and human recombinant CYP3A4 demonstrated a potential use for DMSO-treated HuH-7 cell line as a whole cell system for measuring CYP3A4 inhibition.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of CYP3A4 inhibition and hepatotoxicity using DMSO-treated human hepatoma HuH-7 cells

et al. 2015

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A human hepatoma cell line (HuH-7) was evaluated as a metabolically competent cell model to investigate cytochrome P450 3A4 (CYP3A4) inhibition, induction, and hepatotoxicity. First, CYP3A4 gene expression and activity were determined in HuH-7 cells under three culture conditions: 1-week culture, 3-week culture, or 1% dimethyl sulfoxide (DMSO) treatment. HuH-7 cells treated with DMSO for 2 weeks after confluence expressed the highest CYP3A4 gene expression and activity compared to the other two culture conditions. Furthermore, CYP3A4 activity in DMSO-treated HuH-7 cells was compared to that in a human hepatoma cell line (HepG2/C3A) and human bipotent progenitor cell line (HepaRG), which yielded the following ranking: HepaRG > DMSO-treated HuH-7 >> HepG2/C3A cells. The effects of three known CYP3A4 inhibitors were evaluated using DMSO-treated HuH-7 cells. CYP3A4 enzyme inhibition in HuH-7 cells was further compared to human recombinant CYP3A4, indicating similar potency for reversible inhibitors (IC50 within 2.5 fold), but different potency for the irreversible inhibitor. Next, induction of CYP3A4 activity was compared between DMSO-treated HuH-7 and HepaRG cells using two known inducers. DMSO-treated HuH-7 cells yielded minimal CYP3A4 induction compared to that in the HepaRG cells after 48-h treatments. Finally, the cytotoxicity of five known hepatotoxicants was evaluated in DMSO-treated HuH-7 cells, HepG2/C3A, and HepaRG cells, and significant differences in cytotoxic sensitivity were observed. Overall, DMSO-treated HuH-7 cells are a valuable model for medium- or high-throughput screening of chemicals for CYP3A4 inhibition and hepatotoxicity.

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

Cited by 46 publications

References 43 publications

Inhibition of mTORC2 Induces Cell-Cycle Arrest and Enhances the Cytotoxicity of Doxorubicin by Suppressing MDR1 Expression in HCC Cells

Inhibition of mTORC2 Induces Cell-Cycle Arrest and Enhances the Cytotoxicity of Doxorubicin by Suppressing MDR1 Expression in HCC Cells

Schweinfurthins: Lipid Modulators with Promising Anticancer Activity

Evaluation of CYP3A4 inhibition and hepatotoxicity using DMSO-treated human hepatoma HuH-7 cells

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