Proteomic and transcriptomic study on the action of a cytotoxic saponin (Polyphyllin D): Induction of endoplasmic reticulum stress and mitochondria-mediated apoptotic pathways

Authors

  • Fung-Ming Siu,

    1. Department of Chemistry and Open Laboratory of Chemical Biology of the Institute of Molecular Technology for Drug Discovery and Synthesis, The University of Hong Kong, Hong Kong SAR, China
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  • Dik-Lung Ma,

    1. Department of Chemistry and Open Laboratory of Chemical Biology of the Institute of Molecular Technology for Drug Discovery and Synthesis, The University of Hong Kong, Hong Kong SAR, China
    2. Department of Applied Biology and Chemical Technology and Central Laboratory of the Institute of Molecular Technology for Drug Discovery and Synthesis, The Hong Kong Polytechnic University, Hong Kong SAR, China
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  • Yee-Wai Cheung,

    1. Department of Chemistry and Open Laboratory of Chemical Biology of the Institute of Molecular Technology for Drug Discovery and Synthesis, The University of Hong Kong, Hong Kong SAR, China
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  • Chun-Nam Lok,

    1. Department of Chemistry and Open Laboratory of Chemical Biology of the Institute of Molecular Technology for Drug Discovery and Synthesis, The University of Hong Kong, Hong Kong SAR, China
    2. Department of Anatomy, The University of Hong Kong, Hong Kong SAR, China
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  • Kun Yan,

    1. Department of Chemistry and Open Laboratory of Chemical Biology of the Institute of Molecular Technology for Drug Discovery and Synthesis, The University of Hong Kong, Hong Kong SAR, China
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  • Zhiqi Yang,

    1. Shanghai-Hong Kong Joint Laboratory on Chemical Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China
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  • Mengsu Yang,

    1. Department of Biology and Chemistry, City University of Hong Kong, Hong Kong SAR, China
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  • SongXiao Xu,

    1. Department of Chemistry and Open Laboratory of Chemical Biology of the Institute of Molecular Technology for Drug Discovery and Synthesis, The University of Hong Kong, Hong Kong SAR, China
    2. The Sir Yue Kong Pao Centre for Cancer, Prince of Wales Hospital, Hong Kong SAR, China
    3. Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China
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  • Ben Chi-Bun Ko,

    1. Department of Chemistry and Open Laboratory of Chemical Biology of the Institute of Molecular Technology for Drug Discovery and Synthesis, The University of Hong Kong, Hong Kong SAR, China
    2. The Sir Yue Kong Pao Centre for Cancer, Prince of Wales Hospital, Hong Kong SAR, China
    3. Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China
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  • Qing-Yu He,

    1. Department of Chemistry and Open Laboratory of Chemical Biology of the Institute of Molecular Technology for Drug Discovery and Synthesis, The University of Hong Kong, Hong Kong SAR, China
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  • Chi-Ming Che Professor

    Corresponding author
    1. Department of Chemistry and Open Laboratory of Chemical Biology of the Institute of Molecular Technology for Drug Discovery and Synthesis, The University of Hong Kong, Hong Kong SAR, China
    • Department of Chemistry and Open Laboratory of Chemical Biology of the Institute of Molecular Technology for Drug Discovery and Synthesis, The University of Hong Kong, Pokfulam Road, Hong Kong SAR, China Fax: +852-2857-1586
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Abstract

Polyphyllin D (PD) is a potent cytotoxic saponin found in Paris polyphylla. In the present study, bioinformatic, proteomic and transcriptomic analyses were performed to study the mechanisms of action of PD on human nonsmall cell lung cancer (NSCLC) cell line (NCI-H460). Using a gene expression-based bioinformatic tool (connectivity map), PD was identified as a potential ER stress inducer. Our proteomic and transcriptomic analyses revealed that PD treatment led to upregulation of typical ER stress-related proteins/genes including glucose-regulated protein 78 (BiP/GRP78) and protein disulfide isomerase (PDI). In particular, elevated expression of C/EBP homologous transcription factor (chop) and activation of caspase-4 occurred at early time point (8 h) of PD treatment, signifying an initial ER stress-mediated apoptosis. Induction of tumor suppressor p53, disruption of mitochondrial membrane, activation of caspase-9 and caspase-3 were detected upon prolonged PD treatment. Collectively, these data revealed that PD induced the cytotoxic effect through a mechanism initiated by ER stress followed by mitochondrial apoptotic pathway. The ability of activating two major pathways of apoptosis makes PD an attractive drug lead for anticancer therapeutics.

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