Compound C induces autophagy and apoptosis in parental and hydroquinone-selected malignant leukemia cells through the ROS/p38 MAPK/AMPK/TET2/FOXP3 axis View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2020-01-03

AUTHORS

Jing-Ting Chiou, Chia-Hui Huang, Yuan-Chin Lee, Liang-Jun Wang, Yi-Jun Shi, Ying-Jung Chen, Long-Sen Chang

ABSTRACT

Hydroquinone (HQ), a major metabolic product of benzene, causes acute myeloid leukemia (AML) elicited by benzene exposure. Past studies found that continuous exposure of human AML U937 cells to HQ selectively produces malignant U937/HQ cells in which FOXP3 upregulation modulates malignant progression. Other studies revealed that AMPK promotes TET2 activity on DNA demethylation and that TET2 activity is crucial for upregulating FOXP3 expression. This study was conducted to elucidate whether compound C, an AMPK inhibitor, blocked the AMPK–TET2–FOXP3 axis in AML and in HQ-selected malignant cells. We found higher levels of AMPKα, TET2, and FOXP3 expression in U937/HQ cells compared to U937 cells. Treatment of parental Original Article and HQ-selected malignant U937 cells with compound C induced ROS-mediated p38 MAPK activation, leading to a suppression of AMPKα, TET2, and FOXP3 expression. Moreover, compound C induced apoptosis and mTOR-independent autophagy. The suppression of the autophagic flux inhibited the apoptosis of compound C-treated U937 and U937/HQ cells, whereas co-treatment with rapamycin, a mTOR inhibitor, sensitized the two cell lines to compound C cytotoxicity. Overexpression of AMPKα1 or pretreatment with autophagic inhibitors abrogated compound C-induced autophagy and suppression of TET2 and FOXP3 expression. Restoration of AMPKα1 or FOXP3 expression increased cell survival after treatment with compound C. In conclusion, our results show that compound C suppresses AMPK/TET2 axis-mediated FOXP3 expression and induces autophagy-dependent apoptosis in parental and HQ-selected malignant U937 cells, suggesting that the AMPK/TET2/FOXP3 axis is a promising target for improving AML therapy and attenuating benzene exposure-induced AML progression. More... »

PAGES

315-331

References to SciGraph publications

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  • Identifiers

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    http://scigraph.springernature.com/pub.10.1007/s10565-019-09495-3

    DOI

    http://dx.doi.org/10.1007/s10565-019-09495-3

    DIMENSIONS

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    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/31900833


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    32 schema:description Hydroquinone (HQ), a major metabolic product of benzene, causes acute myeloid leukemia (AML) elicited by benzene exposure. Past studies found that continuous exposure of human AML U937 cells to HQ selectively produces malignant U937/HQ cells in which FOXP3 upregulation modulates malignant progression. Other studies revealed that AMPK promotes TET2 activity on DNA demethylation and that TET2 activity is crucial for upregulating FOXP3 expression. This study was conducted to elucidate whether compound C, an AMPK inhibitor, blocked the AMPK–TET2–FOXP3 axis in AML and in HQ-selected malignant cells. We found higher levels of AMPKα, TET2, and FOXP3 expression in U937/HQ cells compared to U937 cells. Treatment of parental Original Article and HQ-selected malignant U937 cells with compound C induced ROS-mediated p38 MAPK activation, leading to a suppression of AMPKα, TET2, and FOXP3 expression. Moreover, compound C induced apoptosis and mTOR-independent autophagy. The suppression of the autophagic flux inhibited the apoptosis of compound C-treated U937 and U937/HQ cells, whereas co-treatment with rapamycin, a mTOR inhibitor, sensitized the two cell lines to compound C cytotoxicity. Overexpression of AMPKα1 or pretreatment with autophagic inhibitors abrogated compound C-induced autophagy and suppression of TET2 and FOXP3 expression. Restoration of AMPKα1 or FOXP3 expression increased cell survival after treatment with compound C. In conclusion, our results show that compound C suppresses AMPK/TET2 axis-mediated FOXP3 expression and induces autophagy-dependent apoptosis in parental and HQ-selected malignant U937 cells, suggesting that the AMPK/TET2/FOXP3 axis is a promising target for improving AML therapy and attenuating benzene exposure-induced AML progression.
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    39 AML therapy
    40 AMPK
    41 AMPK inhibitor
    42 AMPKα
    43 AMPKα1
    44 C.
    45 DNA demethylation
    46 FOXP3 axis
    47 Foxp3 expression
    48 Foxp3 upregulation
    49 MAPK activation
    50 ROS
    51 TET2
    52 TET2 activity
    53 U937
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    55 activation
    56 activity
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    65 benzene
    66 benzene exposure
    67 cell lines
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    70 compound C
    71 compound C.
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    74 cytotoxicity
    75 demethylation
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    77 expression
    78 flux
    79 high levels
    80 hydroquinone
    81 inhibitors
    82 leukemia
    83 leukemia cells
    84 levels
    85 lines
    86 mTOR inhibitors
    87 mTOR-independent autophagy
    88 major metabolic product
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    93 myeloid leukemia
    94 original articles
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    97 past studies
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