title: Sorafenib inhibits cancer side population cells by targeting c‑Jun N‑terminal kinase signaling.
abstract: Sorafenib is a systemic chemotherapeutic agent for advanced hepatocellular carcinoma (HCC). The aim of the present study was to evaluate the anticancer effect of sorafenib in cancer stem cell‑like cells, such as side population (SP) cells, in HCC and to analyze the signaling pathway for drug‑resistance. To evaluate the anticancer effects of sorafenib, Huh7 and Huh‑BAT cells were treated with sorafenib, fluorouracil (5‑FU), and sorafenib plus 5‑FU. These cells were examined for growth rates, the SP fraction, sphere‑forming efficacy and expression of c‑Jun N‑terminal kinase (JNK) signaling molecules. Sorafenib and 5‑FU treatment decreased growth rates in Huh7 and Huh‑BAT cells; however, the treatments exerted different effects in SP cells and on the expression levels of JNK signaling molecules. Treatment with 5‑FU increased the SP cell number and upregulated the expression of JNK signaling molecules. By contrast, sorafenib decreased the SP cell number and downregulated the expression of JNK signaling molecules. No significant differences in sphere‑forming efficacy were observed subsequent to 5‑FU and sorafenib treatment in Huh7 and Huh‑BAT cells. These results indicate that sorafenib exerted anticancer effects in HCC and SP cells by targeting JNK signaling.
authors.affiliation: Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul 110‑799, Republic of Korea.
authors.forename: Jong Bin
authors.initials: JB
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul 110‑799, Republic of Korea.
authors.forename: Minjong
authors.initials: M
authors.lastname: Lee
authors.affiliation: Biomedical Research Institute, Seoul National University Hospital, Seoul 110‑799, Republic of Korea.
authors.forename: Seo-Young
authors.initials: SY
authors.lastname: Park
authors.affiliation: Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul 110‑799, Republic of Korea.
authors.forename: Seulki
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul 110‑799, Republic of Korea.
authors.forename: Hye Ri
authors.initials: HR
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul 110‑799, Republic of Korea.
authors.forename: Hyo-Suk
authors.initials: HS
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul 110‑799, Republic of Korea.
authors.forename: Jung-Hwan
authors.initials: JH
authors.lastname: Yoon
authors.affiliation: Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul 110‑799, Republic of Korea.
authors.forename: Yoon Jun
authors.initials: YJ
authors.lastname: Kim
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009363:Neoplasm Proteins / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D000077157:Sorafenib
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D010671:Phenylurea Compounds; D016755:Proto-Oncogene Proteins c-jun; D009536:Niacinamide; D000077157:Sorafenib; D005472:Fluorouracil