title: Specific role of JNK in the maintenance of the tumor-initiating capacity of A549 human non-small cell lung cancer cells.
abstract: Deregulation of c-Jun NH2-terminal kinase (JNK) signaling is now increasingly reported in a variety of human malignancies. Non-small cell lung cancer (NSCLC) is among such human malignancies with aberrant JNK activation; yet the exact role(s) of JNK deregulation in NSCLC biology, in particular in vivo, remains unclear. Here, we demonstrated a specific role of JNK in the control of the tumor-initiating capacity of A549 cells derived from human lung adenocarcinoma, a major subtype of NSCLC. Despite its potent inhibitory activity on A549 cell growth in vitro, SP600125, a reversible JNK inhibitor, failed to inhibit the growth of pre-established A549 xenografts in vivo when systemically administered. Nevertheless, the same SP600125 treatment caused a marked reduction in the tumor-initiating population within the A549 tumors, suggesting that JNK may be specifically required in vivo for the maintenance of the tumor-initiating population of tumor cells rather than for proliferation and survival of the entire cell population. Furthermore, A549 cells either pre-treated with SP600125 or transiently transfected with siRNAs against the JNK genes in vitro showed substantially reduced ability to initiate tumor formation upon implantation into nude mice, implying that the cell intrinsic JNK activity of A549 cells is essential for the maintenance of their tumor-initiating capacity. To our knowledge, this is the first demonstration that JNK is involved in the control of the tumor-initiating capacity of NSCLC cells. Our findings also give rise to an intriguing possibility that therapies targeting JNK could contribute to prevention of relapse and/or metastasis of NSCLC through elimination of tumor-initiating cells.
authors.affiliation: Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata 990-9585, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Okada
authors.forename: Keita
authors.initials: K
authors.lastname: Shibuya
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sato
authors.forename: Shizuka
authors.initials: S
authors.lastname: Seino
authors.forename: Eriko
authors.initials: E
authors.lastname: Watanabe
authors.forename: Shuhei
authors.initials: S
authors.lastname: Suzuki
authors.forename: Manabu
authors.initials: M
authors.lastname: Seino
authors.forename: Chifumi
authors.initials: C
authors.lastname: Kitanaka
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics; D064593:Heterografts; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D048055:Mitogen-Activated Protein Kinase 8 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D048056:Mitogen-Activated Protein Kinase 9 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D034622:RNA Interference; D034741:RNA, Small Interfering
chemical_list: D000873:Anthracenes; D034741:RNA, Small Interfering; C432165:pyrazolanthrone; D048056:Mitogen-Activated Protein Kinase 9; D048055:Mitogen-Activated Protein Kinase 8