title: Sulfasalazine attenuates evading anticancer response of CD133-positive hepatocellular carcinoma cells.
abstract: CD133-positive cells in hepatocellular carcinoma (HCC) exhibit cancer stem cell (CSC)-like properties as well as resistance to chemotherapeutic agents and ionizing radiation; however, their function remains unknown. In this paper, we identified a hitherto unknown mechanism to overcome CD133-induced resistance to anticancer therapy.
  
  
  
  We applied an alternative approach to enrich the CD133-positive HCC population by manipulating 3D culture conditions. Defense mechanisms against reactive oxygen species (ROS) in CSC spheroids were evaluated by fluorescence image-based phenotypic screening system. Further, we studied the effect of sulfasalazine on ROS defense system and synergistic therapeutic efficacy of anticancer therapies both in culture and in vivo HCC xenograft mouse model.
  
  
  
  Here, we found that oxidative stress increase CD133 expression in HCC and increased CD133 expression enhanced the capacity of the defense system against ROS, and thereby play a central role in resistance to liver cancer therapy. Moreover, ablation of CD133 attenuated not only the capacity for defense against ROS, but also chemoresistance, in HCC through decreasing glutathione (GSH) levels in vitro. Sulfasalazine, a potent xCT inhibitor that plays an important role in maintaining GSH levels, impaired the ROS defense system and increased the therapeutic efficacy of anticancer therapies in CD133-positive HCC but not CD133-negative HCC in vivo and in vitro.
  
  
  
  These results strongly indicate functional roles for CD133 in ROS defense and in evading anticancer therapies in HCC, and suggest that sulfasalazine, administered in combination with conventional chemotherapy, might be an effective strategy against CD133-positive HCC cells.
authors.affiliation: Cancer Biology Research Laboratory, Institut Pasteur Korea, 16, Daewangpangyo-ro 712 beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, 13488, South Korea.
authors.forename: Yeonhwa
authors.initials: Y
authors.lastname: Song
authors.affiliation: Laboratory of Biochemistry, Division of Life Sciences, Korea University, 145, Anam-ro, Seongbuk-gu, Seoul, 02841, South Korea.
authors.forename: Jaewoo
authors.initials: J
authors.lastname: Jang
authors.affiliation: Department of Medicine, University of Ulsan College of Medicine, 88 Olympic-ro, 43-gil, Songpa-gu, Seoul, 05505, South Korea.
authors.forename: Tae-Hoon
authors.initials: TH
authors.lastname: Shin
authors.affiliation: Department of Medicine, University of Ulsan College of Medicine, 88 Olympic-ro, 43-gil, Songpa-gu, Seoul, 05505, South Korea.|Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro, 43-gil, Songpa-gu, Seoul, 05505, South Korea.
authors.forename: Sang Mun
authors.initials: SM
authors.lastname: Bae
authors.affiliation: Division of Gastroenterology and Hepatology, ASAN Medical center, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, South Korea.
authors.forename: Jin-Sun
authors.initials: JS
authors.lastname: Kim
authors.affiliation: Division of Gastroenterology and Hepatology, ASAN Medical center, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, South Korea.
authors.forename: Kang Mo
authors.initials: KM
authors.lastname: Kim
authors.affiliation: Department of Medicine, University of Ulsan College of Medicine, 88 Olympic-ro, 43-gil, Songpa-gu, Seoul, 05505, South Korea.|Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro, 43-gil, Songpa-gu, Seoul, 05505, South Korea.|Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro, 43-gil, Songpa-gu, Seoul, 05505, South Korea.
authors.forename: Seung-Jae
authors.initials: SJ
authors.lastname: Myung
authors.affiliation: Division of Radiation Oncology, ASAN Medical center, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, South Korea.
authors.forename: Eun Kyung
authors.initials: EK
authors.lastname: Choi
authors.affiliation: Cancer Biology Research Laboratory, Institut Pasteur Korea, 16, Daewangpangyo-ro 712 beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, 13488, South Korea. shr1261@ip-korea.org.
authors.forename: Haeng Ran
authors.initials: HR
authors.lastname: Seo
mesh_terms: D000071916:AC133 Antigen / Q000378:metabolism*; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004358:Drug Therapy; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D012460:Sulfasalazine / Q000008:administration & dosage* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000071916:AC133 Antigen; C000606023:PROM1 protein, human; D017382:Reactive Oxygen Species; D012460:Sulfasalazine
keywords: CD133; Cancer stem cells (CSCs); Hepatocellular carcinoma (HCC); Reactive oxygen species (ROS); Sulfasalazine