title: JNK signaling in hepatocarcinoma cells is associated with the side population upon treatment with anticancer drugs.
abstract: Liver cancer is one of the most drug-resistant cancer types, and cancer stem cells are related to drug resistance. c-Jun-N-terminal kinase (JNK) signaling is involved in drug resistance, and the side population of cells (SP cells) can be used as a model to study liver cancer stem cells. We sought to evaluate the relationship between SP cells and JNK signaling in hepatocarcinoma cells. For this purpose, we examined cell proliferation and the SP cell ratio following treatment of Huh7 cells with the anticancer drugs 5-fluorouracil (5-FU) and paclitaxel. The expression of phospho-stress-activated protein kinase (SAPK)/JNK in the treated cells was evaluated using immunoblotting. 5-FU and paclitaxel treatment increased the number of SP cells and JNK phosphorylation, and decreased cell survival. Huh7 and HepG2 cells were also treated with SP600125, a JNK inhibitor, to study the relationship between SP cells and JNK signaling. The increase in the number of SP cells and the SAPK/JNK and c-Jun phosphorylation was reverted by SP600125 treatment in these cells. We also used immunohistochemistry and showed that SAPK/JNK and c-Jun phosphorylation are increased in hepatocarcinoma tissues. In conclusion, our results demonstrate that the number of SP cells and SAPK/JNK phosphorylation are increased upon treatment with anticancer drugs, and that this increase is blocked by inhibition of JNK signaling. These findings suggest that drug resistance in liver cancer may involve an increase in the number of SP cells following JNK activation.
authors.affiliation: Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Jongno-gu, Seoul 110-799, Republic of Korea.
authors.forename: Jong Bin
authors.initials: JB
authors.lastname: Kim
authors.affiliation: Biomedical Research Institute, Seoul National University Hospital, Jongno-gu, 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, Jongno-gu, 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, Jongno-gu, Seoul 110-799, Republic of Korea.
authors.forename: Yeon Hwa
authors.initials: YH
authors.lastname: Ahn
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Jongno-gu, Seoul 110-799, Republic of Korea.
authors.forename: Hyeon-Gun
authors.initials: HG
authors.lastname: Jee
authors.affiliation: Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Jongno-gu, Seoul 110-799, Republic of Korea.
authors.forename: Jeong-Hoon
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Jongno-gu, Seoul 110-799, Republic of Korea.
authors.forename: Su Jong
authors.initials: SJ
authors.lastname: Yu
authors.affiliation: Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Jongno-gu, 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, Jongno-gu, Seoul 110-799, Republic of Korea.
authors.forename: Minjong
authors.initials: M
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Jongno-gu, 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, Jongno-gu, Seoul 110-799, Republic of Korea.
authors.forename: Yoon Jun
authors.initials: YJ
authors.lastname: Kim
mesh_terms: D000873:Anthracenes / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D020935:MAP Kinase Signaling System; D017239:Paclitaxel / Q000494:pharmacology; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D058985:Side-Population Cells / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000873:Anthracenes; D000970:Antineoplastic Agents; D016755:Proto-Oncogene Proteins c-jun; C432165:pyrazolanthrone; D048670:MAP Kinase Kinase 4; D017239:Paclitaxel; D005472:Fluorouracil