caa a22 4500 445336722 CHVBK 20180317142758.0 cr unu---uuuuu 170323e20110501xx s 000 0 eng 10.1245/s10434-010-1444-y doi (NATIONALLICENCE)springer-10.1245/s10434-010-1444-y Normoxically Overexpressed Hypoxia Inducible Factor 1-Alpha is Involved in Arsenic Trioxide Resistance Acquisition in Hepatocellular Carcinoma [Elektronische Daten] [Jia-Nien Tung, Ya-Wen Cheng, Chung-Huei Hsu, Tsan-Zon Liu, Pei-Ying Hsieh, Lai-Lei Ting, Hui-Ling Ko, Yu-Jia Chang, Jeng-Fong Chiou, Alexander Wu] Background: The aim of this study was to examine the underlying signaling mechanisms of arsenic trioxide (ATO)-mediated anticancer effects and the responsible biomarker(s) for the acquired resistance in human heptatocellular carcinoma (HCC). Materials and Methods: The therapeutic effects of ATO were examined using 2 characteristically distinct HCC cell lines, Hep-J5 (overexpressing HIF-1α/GRP78) and SK-Hep-1 (the matched control). ATO-mediated proliferation inhibition, oxidative stress, and apoptosis were analyzed using flowcytometric analysis and western blotting. The role of HIF-1α and GRP78 in HCC resistance to ATO treatment was determined using RNA silencing and inhibitor approaches. Results: SK-Hep-1 cells, lacking both HIF-1α and GRP78 expressions were responsive to ATO-induced apoptosis via an oxidative-nitrosative mechanism. Intracellular glutathione depletion and lipid peroxidation have been identified as the early cascade of events preceding apoptosis via cytochrome c release and the severe drop of mitochondrial membrane potential (MMP). Conversely, Hep-J5 cells, with normoxic coexpression of HIF-1α and GRP78, were resistant to ATO-induced apoptosis. GRP78-silenced Hep-J5 cells remained resistant to ATO treatment. In contrast, ATO resistance in Hep-J5 cells was overcome by the addition of YC-1, a HIF-1α inhibitor. Conclusions: HIF-1α was identified as the major positive modifier for ATO resistance acquisition in HCC, and it represents a prime molecular target for overcoming ATO resistance. Society of Surgical Oncology, 2010 Tung Jia-Nien Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan aut Cheng Ya-Wen Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan aut Hsu Chung-Huei Department of Endocrinology and Metabolism, School of Medicine, Taipei Medical University, Taipei, Taiwan aut Liu Tsan-Zon Translational Research Laboratory, Cancer Center, Taipei Medical University Hospital, Taipei, Taiwan aut Hsieh Pei-Ying Translational Research Laboratory, Cancer Center, Taipei Medical University Hospital, Taipei, Taiwan aut Ting Lai-Lei Department of Radiation, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan aut Ko Hui-Ling Department of Radiation, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan aut Chang Yu-Jia Department of Clinical Medicine, Taipei Medical University, Taipei, Taiwan aut Chiou Jeng-Fong Translational Research Laboratory, Cancer Center, Taipei Medical University Hospital, Taipei, Taiwan aut Wu Alexander Translational Research Laboratory, Cancer Center, Taipei Medical University Hospital, Taipei, Taiwan aut Annals of Surgical Oncology Springer-Verlag 18/5(2011-05-01), 1492-1500 1068-9265 18:5<1492 2011 18 10434 https://doi.org/10.1245/s10434-010-1444-y text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1245/s10434-010-1444-y text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Tung Jia-Nien Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan aut NATIONALLICENCE 700 1- Cheng Ya-Wen Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan aut NATIONALLICENCE 700 1- Hsu Chung-Huei Department of Endocrinology and Metabolism, School of Medicine, Taipei Medical University, Taipei, Taiwan aut NATIONALLICENCE 700 1- Liu Tsan-Zon Translational Research Laboratory, Cancer Center, Taipei Medical University Hospital, Taipei, Taiwan aut NATIONALLICENCE 700 1- Hsieh Pei-Ying Translational Research Laboratory, Cancer Center, Taipei Medical University Hospital, Taipei, Taiwan aut NATIONALLICENCE 700 1- Ting Lai-Lei Department of Radiation, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan aut NATIONALLICENCE 700 1- Ko Hui-Ling Department of Radiation, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan aut NATIONALLICENCE 700 1- Chang Yu-Jia Department of Clinical Medicine, Taipei Medical University, Taipei, Taiwan aut NATIONALLICENCE 700 1- Chiou Jeng-Fong Translational Research Laboratory, Cancer Center, Taipei Medical University Hospital, Taipei, Taiwan aut NATIONALLICENCE 700 1- Wu Alexander Translational Research Laboratory, Cancer Center, Taipei Medical University Hospital, Taipei, Taiwan aut NATIONALLICENCE 773 0- Annals of Surgical Oncology Springer-Verlag 18/5(2011-05-01), 1492-1500 1068-9265 18:5<1492 2011 18 10434 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer