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Armillaridin induces autophagy-associated cell death in human chronic myelogenous leukemia K562 cells

Tumor Biology volume 37, pages 14291–14300 (2016)Cite this article

Abstract

Armillaridin (AM) is an aromatic ester compound isolated from Armillaria mellea. Treatment with AM markedly reduced the viability of human chronic myelogenous leukemia K562, chronic erythroleukemia HEL 92.1.7, and acute monoblastic leukemia U937 cells, but not normal human monocytes, in a dose- and time-dependent manner. Treatment of K562 cells with AM caused changes characteristic of autophagy. Only a small amount of AM-treated K562 cells exhibited apoptosis. By contrast, AM treatment resulted in extensive apoptotic features in U937 and HEL 92.1.7 cells without evident autophagy. The autophagy of K562 cells induced by AM involved autophagic flux, including autophagosome induction, the processing of autophagosome-lysosome fusion and downregulation of BCL2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3). By bcr-abl knockdown, the growth inhibition of K562 cells caused by AM was partially blocked, suggesting that AM-induced cell death might be a bcr-abl-dependent mode of autophagy-associated cell death. In conclusion, AM is capable of inhibiting growth and inducing autophagy-associated cell death in K562 cells, but not in normal monocytes. It may have potential to be developed as a novel therapeutic agent against leukemia.

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Abbreviations

AM:

Armillaridin

BNIP3:

BCL2/adenovirus E1B 19 kDa interacting protein 3

CML:

Chronic myelogenous leukemia

CQ:

Chloroquine

3-MA:

3-Methyladenine

STI-571:

Signal transduction inhibitor-571

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Acknowledgments

We want to thank Dr. King-Song Jeng and the National RNAi Core Facility, Academia Sinica, Taiwan, for shRNA knockdown techniques, the pTRC-905 vector, and the pTRC-905-shBCR constructions. This work was supported by grant NSC98-2323-B-241 from the National Science Council, Taiwan, and grant 09MMHIS027 and MMH-E-105-13, E-104-13 from MacKay Memorial Hospital, Taiwan.

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Affiliations

  1. Institute of Traditional Medicine, National Yang-Ming University, Taipei, 11221, Taiwan

    Wen-Han Chang & Yu-Jen Chen

  2. Department of Healthcare Center, MacKay Memorial Hospital, New Taipei City, 25173, Taiwan

    Wen-Han Chang

  3. Department of Bioscience Technology, College of Health Science, Chang Jung Christian University, Tainan, 71101, Taiwan

    Huey-Lan Huang

  4. Department of Life Science and Institute of Zoology, National Taiwan University, Taipei, 10617, Taiwan

    Wei-Pang Huang

  5. Department of Biotechnology, Hungkuang University, No.1018, Sec. 6, Taiwan Boulevard, Shalu Dist., Taichung City, 43302, Taiwan

    Chien-Chih Chen

  6. Department of Medical Research, MacKay Memorial Hospital, No.92, Section 2, Zhongshan N. Rd., Zhongshan District, Taipei City, 10449, Taiwan

    Yu-Jen Chen

  7. Department of Radiation Oncology, MacKay Memorial Hospital, No.92, Section 2, Zhongshan N. Rd., Zhongshan District, Taipei City, 10449, Taiwan

    Yu-Jen Chen

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  1. Wen-Han Chang
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  2. Huey-Lan Huang
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  3. Wei-Pang Huang
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  4. Chien-Chih Chen
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Correspondence to Chien-Chih Chen or Yu-Jen Chen.

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Electronic supplementary material

Supplemental Figure 1.
figure 10

Effect of armillaridin on BCR-ABL expression on K562 cells. Cells were untreated, treated with 0.1% DMSO (solvent), 10 μM armillaridin for 24 hours or starvation for 6 hours. Protein extracts from whole cells were subjected to Western blotting. Data from three separate experiments showed similar trend. No significant differences on the expression of BCR-ABL were found between control and armillaridin treatment. (GIF 175 kb)

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Chang, WH., Huang, HL., Huang, WP. et al. Armillaridin induces autophagy-associated cell death in human chronic myelogenous leukemia K562 cells. Tumor Biol. 37, 14291–14300 (2016). https://doi.org/10.1007/s13277-016-5208-6

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  • DOI: https://doi.org/10.1007/s13277-016-5208-6

Keywords

  • Armillaridin
  • Autophagy
  • bcr-abl
  • BNIP3
  • Chronic myelogenous leukemia