JNK/AP-1 activation contributes to tetrandrine resistance in T-cell acute lymphoblastic leukaemia

T-cell acute lymphoblastic leukaemia （T-ALL） is a challenging malignancy with a high relapse rate attributed to drug resistance. Tetrandrine （TET）, a bisbenzylisoquinoline alkaloid extracted from a Chinese herb, is a potential anti-cancer and anti-leukaemic drug. In this study we investigated the me...

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Bibliographic Details
Published in:Acta pharmacologica Sinica 2017-08, Vol.38 (8), p.1171-1183
Main Authors: Liou, Jun-Ting, Lin, Chin-Sheng, Liao, Yu-Cheng, Ho, Ling-Jun, Yang, Shih-Ping, Lai, Jenn-Haung
Format: Article
Language:English
Subjects:
Activation
Activator protein 1
Acute lymphoblastic leukemia
Antineoplastic Agents, Phytogenic - pharmacology
AP-1
Benzylisoquinolines - pharmacology
Biotechnology
Bisbenzylisoquinoline
Blotting, Western
c-Jun protein
Cancer
Cell Line, Tumor
Cell lines
Drug resistance
Drug Resistance, Neoplasm
Extracellular signal-regulated kinase
Flow Cytometry
Humans
JNK
JNK protein
Jurkat Cells - drug effects
Jurkat细胞
Leukemia
Lymphocytes T
Malignancy
MAP Kinase Signaling System - physiology
Original
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - drug therapy
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - metabolism
Resistance factors
T cell receptors
Tetrandrine
Transcription factors
T细胞
四环素抗性
急性
淋巴细胞性白血病
细胞外信号调节激酶
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Summary:T-cell acute lymphoblastic leukaemia （T-ALL） is a challenging malignancy with a high relapse rate attributed to drug resistance. Tetrandrine （TET）, a bisbenzylisoquinoline alkaloid extracted from a Chinese herb, is a potential anti-cancer and anti-leukaemic drug. In this study we investigated the mechanisms of TET resistance in T-ALL cells in vitro. Among the four T-ALL cell lines tested, Jurkat and CEM ceils exhibited the lowest and highest resistance to TET with IC50 values at 24 h of 4.31±0.12 and 16.53±3.32 pmol/L, respectively. When treated with TET, the activity of transcription factor activator protein 1 （AP-1） was significantly decreased in Jurkat cells but nearly constant in CEM cells. To avoid cell-specific variation in drug resistance and transcription factor activities, we established a TET-R Jurkat subclone with the estimated IC50 value of 10.90±92 pmol/L by exposing the cells to increasing concentrations of TET. Interestingly, when treated with TET, TET-R Jurkat cells exhibited enhanced AP-1 and NF-κB activity, along with upregulation of c-Jun N-terminal kinase （JNK） and extracellular signal-regulated kinase （ERK） signaling pathways, whereas the expression of P-gp was not altered. Selective inhibition of JNK but not ERK suppressed AP-1 activity and TET resistance in TET-R Jurkat cells and in CEM cells. These results demonstrate that Jurkat cells acquire TET resistance through activation of the JNK/AP-1 pathway but not through P-gp expression. The JNK/AP-1 pathway may be a potential therapeutic target in relapsed T-ALL.
ISSN:1671-4083
1745-7254
DOI:10.1038/aps.2017.26