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Blood, 15 February 2005, Vol. 105, No. 4, pp. 1724-1733. Prepublished online as a Blood First Edition Paper on October 14, 2004; DOI 10.1182/blood-2004-07-2938. This Article Full Text (PDF) All Versions of this Article: 2004-07-2938v1 105/4/1724    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Park, M.-T. Articles by Lee, S.-J. Search for Related Content PubMed PubMed Citation Articles by Park, M.-T. Articles by Lee, S.-J. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted July 30, 2004 Accepted October 6, 2004 Phytosphingosine in combination with ionizing radiation enhances apoptotic cell death in radiation-resistant cancer cells through ROS-dependent and -independent AIF release Moon-Taek Park, Min-Jung Kim, Young-Hee Kang, Soon-Young Choi, Jae-Hoon Lee, Jung-A Choi, Chang-Mo Kang, Chul-Koo Cho, Seongman Kang, Sangwoo Bae, Yun-Sil Lee, Hee Y Chung, and Su-Jae Lee* Laboratory of Radiation Effect, Korea Institute of Radiological & Medical Sciences, Seoul, Korea; Graduate School of Biotechnology, Korea University, Seoul, Korea Laboratory of Radiation Effect, Korea Institute of Radiological & Medical Sciences, Seoul, Korea Graduate School of Biotechnology, Korea University, Seoul, Korea Department of Microbiology, College of Medicine, Hanyang University, Seoul, Korea * Corresponding author; email: sjlee{at}kcch.re.kr. The use of chemical modifiers as radiosensitizers in combination with low-dose irradiation may increase the therapeutic effect on cancer by overcoming a high apoptotic threshold. Here, we show that phytosphingosine treatment in combination with -radiation enhanced apoptotic cell death of radiation-resistant human T-cell lymphoma in a caspase-independent manner. Combination treatment induced an increase in intracellular reactive oxygen species (ROS) level, mitochondrial relocalization of Bax, PARP-1 activation, and nuclear translocation of apoptosis inducing factor (AIF). siRNA targeting of AIF effectively protected cells from the combination treatment-induced cell death. An antioxidant, NAC inhibited Bax relocalization and AIF translocation, but not PARP-1 activation. Moreover, transfection of Bax-siRNA significantly inhibited AIF translocation. Pre-treatment of PARP-1 inhibitor, DPQ, or PARP-1-siRNA also partially attenuated AIF translocation whereas the same treatment did not affect intracellular ROS level and Bax redistribution. Taken together, these results demonstrate that enhancement of cell death of radiation-resistant cancer cells by phytosphingosine treatment in combination with -radiation is mediated by nuclear translocation of AIF which is in turn mediated both by ROS-dependent Bax relocalization and ROSindependent PARP-1 activation. The molecular signaling pathways that we elucidated in this study may provide potential drug targets for radiation sensitization of cancers refractive to radiation therapy. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J.-Y. Byun, M.-J. Kim, D.-Y. Eum, C.-H. Yoon, W.-D. Seo, K. H. Park, J.-W. Hyun, Y.-S. Lee, J.-S. Lee, M.-Y. Yoon, et al. Reactive Oxygen Species-Dependent Activation of Bax and Poly(ADP-ribose) Polymerase-1 Is Required for Mitochondrial Cell Death Induced by Triterpenoid Pristimerin in Human Cervical Cancer Cells Mol. Pharmacol., October 1, 2009; 76(4): 734 - 744. [Abstract] [Full Text] [PDF] U. M. Schneiders, L. Schyschka, A. Rudy, and A. M. Vollmar BH3-only proteins Mcl-1 and Bim as well as endonuclease G are targeted in spongistatin 1-induced apoptosis in breast cancer cells Mol. Cancer Ther., October 1, 2009; 8(10): 2914 - 2925. [Abstract] [Full Text] [PDF] G. Kroemer, L. Galluzzi, and C. Brenner Mitochondrial Membrane Permeabilization in Cell Death Physiol Rev, January 1, 2007; 87(1): 99 - 163. [Abstract] [Full Text] [PDF] M.-T. Park, Y.-H. Kang, I.-C. Park, C.-H. Kim, Y.-S. Lee, H. Y. Chung, and S.-J. Lee Combination treatment with arsenic trioxide and phytosphingosine enhances apoptotic cell death in arsenic trioxide-resistant cancer cells Mol. Cancer Ther., January 1, 2007; 6(1): 82 - 92. [Abstract] [Full Text] [PDF] P. O. Hassa, S. S. Haenni, M. Elser, and M. O. Hottiger Nuclear ADP-Ribosylation Reactions in Mammalian Cells: Where Are We Today and Where Are We Going? Microbiol. Mol. Biol. Rev., September 1, 2006; 70(3): 789 - 829. [Abstract] [Full Text] [PDF] E. Yamasaki, A. Wada, A. Kumatori, I. Nakagawa, J. Funao, M. Nakayama, J. Hisatsune, M. Kimura, J. Moss, and T. Hirayama Helicobacter pylori Vacuolating Cytotoxin Induces Activation of the Proapoptotic Proteins Bax and Bak, Leading to Cytochrome c Release and Cell Death, Independent of Vacuolation J. Biol. Chem., April 21, 2006; 281(16): 11250 - 11259. [Abstract] [Full Text] [PDF]

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