Interplay of reactive oxygen species, intracellular Ca2+ and mitochondrial homeostasis in the apoptosis of prostate cancer cells by deoxypodophyllotoxin

Authors

  • Kwang-Youn Kim,

    1. Department of Microbiology and Immunology, Pusan National University School of Medicine, Yangsan 626-870, Republic of Korea
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  • Hyo-Jin Cho,

    1. Brain Disease Research Center, Ajou University School of Medicine, Suwon 443-749, Republic of Korea
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  • Sun-Nyoung Yu,

    1. Department of Microbiology and Immunology, Pusan National University School of Medicine, Yangsan 626-870, Republic of Korea
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  • Sang-Hun Kim,

    1. Department of Microbiology and Immunology, Pusan National University School of Medicine, Yangsan 626-870, Republic of Korea
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  • Hak-Sun Yu,

    1. Department of Parasitology, Pusan National University School of Medicine, Yangsan 626-870, Republic of Korea
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  • Yeong-Min Park,

    1. Department of Microbiology and Immunology, Pusan National University School of Medicine, Yangsan 626-870, Republic of Korea
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  • Nooshin Mirkheshti,

    1. Department of Molecular Medicine and Institute of Biotechnology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78245
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  • So Young Kim,

    1. Department of Molecular Medicine and Institute of Biotechnology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78245
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  • Chung Seog Song,

    1. Department of Molecular Medicine and Institute of Biotechnology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78245
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  • Bandana Chatterjee,

    Corresponding author
    1. Department of Molecular Medicine and Institute of Biotechnology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78245
    2. South Texas Veterans Health Care System, San Antonio, Texas 78229
    • Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, 15355 Lambda Drive, San Antonio, TX 78245.
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  • Soon-Cheol Ahn

    Corresponding author
    1. Department of Microbiology and Immunology, Pusan National University School of Medicine, Yangsan 626-870, Republic of Korea
    2. Department of Molecular Medicine and Institute of Biotechnology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78245
    3. Medical Research Institute, Pusan National University, Yangsan 626-870, Republic of Korea
    • Department of Microbiology and Immunology, Pusan National University School of Medicine, Yangsan 626-870, Republic of Korea.
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  • Conflict of interest: none.

  • Kwang-Youn Kim and Hyo-Jin Cho contributed equally to this work.

Abstract

The limited treatment option for recurrent prostate cancer and the eventual resistance to conventional chemotherapy drugs has fueled continued interest in finding new anti-neoplastic agents of natural product origin. We previously reported anti-proliferative activity of deoxypodophyllotoxin (DPT) on human prostate cancer cells. Using the PC-3 cell model of human prostate cancer, the present study reveals that DPT induced apoptosis via a caspase-3-dependent pathway that is activated due to dysregulated mitochondrial function. DPT-treated cells showed accumulation of the reactive oxygen species (ROS), intracellular Camath image surge, increased mitochondrial membrane potential (MMP, ΔΨm), Bax protein translocation to mitochondria and cytochrome c release to the cytoplasm. This resulted in caspase-3 activation, which in turn induced apoptosis. The antioxidant N-acetylcysteine (NAC) reduced ROS accumulation, MMP and Camath image surge, on the other hand the Ca2+ chelator BAPTA inhibited the Camath image overload and MMP without affecting the increase of ROS, indicating that the generation of ROS occurred prior to Ca2+ flux. This suggested that both ROS and Camath image signaling play roles in the increased MMP via Camath image-dependent and/or -independent mechanisms, since ΔΨm elevation was reversed by NAC and BAPTA. This study provides the first evidence for the involvement of both ROS- and Camath image-activated signals in the disruption of mitochondrial homeostasis and the precedence of ROS production over the failure of Ca2+ flux homeostasis. J. Cell. Biochem. 114: 1124–1134, 2013. © 2012 Wiley Periodicals, Inc.

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