title: Critical role of STAT3 in IL-6-mediated drug resistance in human neuroblastoma.
abstract: Drug resistance is a major cause of treatment failure in cancer. Here, we have evaluated the role of STAT3 in environment-mediated drug resistance (EMDR) in human neuroblastoma. We determined that STAT3 was not constitutively active in most neuroblastoma cell lines but was rapidly activated upon treatment with interleukin (IL)-6 alone and in combination with the soluble IL-6 receptor (sIL-6R). Treatment of neuroblastoma cells with IL-6 protected them from drug-induced apoptosis in a STAT3-dependent manner because the protective effect of IL-6 was abrogated in the presence of a STAT3 inhibitor and upon STAT3 knockdown. STAT3 was necessary for the upregulation of several survival factors such as survivin (BIRC5) and Bcl-xL (BCL2L1) when cells were exposed to IL-6. Importantly, IL-6-mediated STAT3 activation was enhanced by sIL-6R produced by human monocytes, pointing to an important function of monocytes in promoting IL-6-mediated EMDR. Our data also point to the presence of reciprocal activation of STAT3 between tumor cells and bone marrow stromal cells including not only monocytes but also regulatory T cells (Treg) and nonmyeloid stromal cells. Thus, the data identify an IL-6/sIL-6R/STAT3 interactive pathway between neuroblastoma cells and their microenvironment that contributes to drug resistance.
authors: Division of Hematology-Oncology, Department of Pediatrics, Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
authors: Tasnim
authors: T
authors: Ara
authors: Rie
authors: R
authors: Nakata
authors: Michael A
authors: MA
authors: Sheard
authors: Hiroyuki
authors: H
authors: Shimada
authors: Ralf
authors: R
authors: Buettner
authors: Susan G
authors: SG
authors: Groshen
authors: Lingyun
authors: L
authors: Ji
authors: Hua
authors: H
authors: Yu
authors: Richard
authors: R
authors: Jove
authors: Robert C
authors: RC
authors: Seeger
authors: Yves A
authors: YA
authors: DeClerck
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001859:Bone Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000556:secondary; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018920:Coculture Techniques; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015850:Interleukin-6 / Q000502:physiology*; D008558:Melphalan / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism; D009447:Neuroblastoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000502:physiology*; D015854:Up-Regulation
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C508600:IL6 protein, human; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D005047:Etoposide; D008558:Melphalan
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