한빛사논문
- 조회3,563
Abstract
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, and Su-Jae Lee
From the Laboratory of Radiation Effect, Korea Institute of Radiological and Medical Sciences; Graduate School of Biotechnology, Korea University; and Department of Microbiology, College of Medicine, Hanyang University, Seoul, Korea.
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 
-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 -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. (Blood. 2005;105:1724-1733)
논문정보
- Research article
- 2005년 02월 (BRIC 등록일 )
- 국내 연구진
- 생명과학 > 노화/암생물학
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