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JNK and ERK mitogen-activated protein kinases mediate THDA-induced apoptosis in K562 cells

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Abstract

2-(6-(2-thieanisyl)-3(Z)-hexen-1, 5-diynyl) aniline (THDA), an enediyne compound, was identified in our laboratory as a novel antineoplastic agent against human leukemia K562 cells. THDA-induced apoptosis was associated with the upregulation of Bax, downregulation of X-linked inhibitor of apoptosis (XIAP), as well as the activation of caspase-3 and caspase-9. In addition, the mitogen-activated protein family kinases, including c-Jun N-terminal kinase (JNK) and extracellular signal-regulated protein kinase (ERK) kinases, and the transcription factor c-Jun were all activated by phosphorylation after 6 h exposure to THDA. Phosphorylation (activation) of JNK and ERK kinases by THDA was blocked by an ERK inhibitor, PD98059, or a JNK inhibitor, JNK-1, respectively, suggesting that THDA-induced apoptosis in K562 cells is ERK and JNK dependent. Moreover, the blockade of ERK and JNK also attenuated the modulation of Bax and XIAP, as well as the activation of caspase-3 and caspase-9 induced by THDA. These findings suggest that the activation of JNK and ERK is involved in the THDA-induced apoptosis of K562 cells. Therefore, this investigation, for the first time, uncovered the biological properties of this novel antitumor enediyne.

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Abbreviations

THDA:

2-(6-(2-thieanisyl)-3(Z)-hexen-1, 5-diynyl) aniline

MTT:

3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide

MAPK:

mitogen-activated protein kinase

ERK:

extracellar signal-regulated protein kinase

JNK:

c-Jun N-terminal kinase

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Acknowledgments

This work was supported by grant NSC 93-2113-M-037–003 from the National Science Council, ROC, and a grant of the National Sun Yat-Sen University–Kaohsiung Medical University Joint Research Center.

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Authors and Affiliations

  1. Faculty of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung, 807, Taiwan, Republic of China

    Sheng-Huei Yang, Zchong-Zcho Wu, Ching-Ming Chien, Yu-Hsiang Lo, Ming-Jung Wu & Shinne-Ren Lin

  2. Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, 804, Taiwan, Republic of China

    Long-Sen Chang

  3. National Sun Yat-Sen University–Kaohsiung Medical University Joint Research Center, Kaohsiung, Taiwan, Republic of China

    Long-Sen Chang & Shinne-Ren Lin

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  1. Sheng-Huei Yang
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  2. Zchong-Zcho Wu
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  3. Ching-Ming Chien
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  4. Yu-Hsiang Lo
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  5. Ming-Jung Wu
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Correspondence to Shinne-Ren Lin.

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Yang, SH., Wu, ZZ., Chien, CM. et al. JNK and ERK mitogen-activated protein kinases mediate THDA-induced apoptosis in K562 cells. Cell Biol Toxicol 24, 291–302 (2008). https://doi.org/10.1007/s10565-007-9038-6

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  • DOI: https://doi.org/10.1007/s10565-007-9038-6

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