title: Blockade of interleukin-6 receptor suppresses the proliferation of H460             lung cancer stem cells.
abstract: IL-6/6R signaling is closely associated with tumor growth and poor prognosis.             Although there is evidence that interleukin-6 receptor (IL-6R)-mediated signaling             promotes the growth and malignancy of cancer, the role of IL-6R in cancer stem             cells (CSCs) is poorly defined. This study investigated the role of IL-6R in the             proliferation of CSCs. Sphere-forming cells were isolated from the H460 non-small             cell lung cancer (NSCLC) cell line and identified as CSCs using confocal microscopy,             RT-PCR and WST-1 assay. The H460 spheres demonstrated the typical characteristics             of CSCs, including CD133 expression, upregulation of Nanog, self-renewal, and             drug resistance to methotrexate (MTX) and fluorouracil (5-FU). The release of             IL-6R and its ligand, IL-6, were quantitatively determined and compared between             CSCs and non-CSCs. The concentration of soluble IL-6R (sIL-6R) was remarkably             high in CSCs compared to that in non-CSCs. Furthermore, significant upregulation             of the IL-6R gene was also observed in the CSCs. The growth of CSCs was significantly             inhibited by transfection with IL-6R small-interfering RNA (siRNA), as well as             with the IL-6R monoclonal antibody (mAb). In addition, blocking both IL-6R and             IL-6 using siRNA or mAbs intensified the inhibition of CSC proliferation. These             findings indicate that IL-6R is present in CSCs and has an important role in the             proliferation of CSCs in the H460 lung cancer cell line. Therefore, we suggest             that IL-6R is both a viable target for the development of CSC-directed lung cancer             therapeutics and a potential CSC marker in NSCLC.
authors.affiliation: Department of Veterinary Pharmacology and Toxicology, College                     of Veterinary Medicine, Konkuk University, Seoul 143-701, Republic of                     Korea.
authors.forename: Hee
authors.initials: H
authors.lastname: Yi
authors.forename: Hee-Jung
authors.initials: HJ
authors.lastname: Cho
authors.forename: Soo-Min
authors.initials: SM
authors.lastname: Cho
authors.forename: Kyul
authors.initials: K
authors.lastname: Jo
authors.forename: Jin-A
authors.initials: JA
authors.lastname: Park
authors.forename: Na-Hyun
authors.initials: NH
authors.lastname: Kim
authors.forename: Gordon L
authors.initials: GL
authors.lastname: Amidon
authors.forename: Jin-Suk
authors.initials: JS
authors.lastname: Kim
authors.forename: Ho-Chul
authors.initials: HC
authors.lastname: Shin
mesh_terms: D057134:Antibodies, Neutralizing / Q000494:pharmacology; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005472:Fluorouracil / Q000494:pharmacology; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008175:Lung Neoplasms; D008727:Methotrexate / Q000494:pharmacology; D000071317:Nanog Homeobox Protein; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000502:physiology*; D034622:RNA Interference; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D018874:Spheroids, Cellular / Q000378:metabolism / Q000502:physiology; D015854:Up-Regulation
chemical_list: D057134:Antibodies, Neutralizing; D000964:Antimetabolites, Antineoplastic; D018398:Homeodomain Proteins; C508600:IL6 protein, human; D015850:Interleukin-6; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D019947:Receptors, Interleukin-6; D005472:Fluorouracil; D008727:Methotrexate