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 Yong Chung, Su Jae Lee

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97 Citations (Scopus)

Abstract

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 showed that phytosphingosine treatment in combination with γ-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 B-cell lymphoma-2(Bcl-2)- associated X protein (Bax), poly-adenosine diphosphate (ADP)-ribose polymerase 1 (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, N-acetyl-L-cysteine (NAC), inhibited Bax relocalization and AIF translocation but not PARP-1 activation. Moreover, transfection of Bax-siRNA significantly inhibited AIF translocation. Pretreatment of PARP-1 inhibitor, DPQ (3,4-dihydro-5-[4-(1-piperidinyl)-butoxy]- 1(2H)-isoquinolinone), 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 γ-radiation is mediated by nuclear translocation of AIF, which is in turn mediated both by ROS-dependent Bax relocalization and ROS-independent 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.

Original languageEnglish
Pages (from-to)1724-1733
Number of pages10
JournalBlood
Volume105
Issue number4
DOIs
Publication statusPublished - 2005 Feb 15

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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  • Cite this

    Park, M. T., Kim, M. J., Kang, Y. H., Choi, S. Y., Lee, J. H., Choi, J. A., Kang, C. M., Cho, C. K., Kang, S., Bae, S., Lee, Y. S., Chung, H. Y., & Lee, S. J. (2005). Phytosphingosine in combination with ionizing radiation enhances apoptotic cell death in radiation-resistant cancer cells through ROS-dependent and -independent AIF release. Blood, 105(4), 1724-1733. https://doi.org/10.1182/blood-2004-07-2938