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: Tasnim Ara, Rie Nakata, Michael A Sheard, Hiroyuki Shimada, Ralf Buettner, Susan G Groshen, Lingyun Ji, Hua Yu, Richard Jove, Robert C Seeger, Yves A DeClerck
• Journal: Cancer research (Cancer Res) Vol. 73 Issue 13 Pg. 3852-64 (Jul 01 2013) ISSN: 1538-7445 [Electronic] United States
• PMID: 23633489 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2013 AACR.

Chemical References

• Antineoplastic Agents, Phytogenic
• IL6 protein, human
• Interleukin-6
• Receptors, Interleukin-6
• STAT3 Transcription Factor
• STAT3 protein, human
• Etoposide
• Melphalan

Topics

• Antineoplastic Agents, Phytogenic (pharmacology)
• Apoptosis (drug effects)
• Bone Neoplasms (drug therapy, metabolism, secondary)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Coculture Techniques
• Drug Resistance, Neoplasm
• Etoposide (pharmacology)
• Gene Expression Regulation, Neoplastic
• Humans
• Interleukin-6 (physiology)
• Melphalan (pharmacology)
• Membrane Potential, Mitochondrial (drug effects)
• Mesenchymal Stem Cells (metabolism)
• Monocytes (metabolism)
• Neuroblastoma (drug therapy, metabolism, pathology)
• Receptors, Interleukin-6 (metabolism)
• STAT3 Transcription Factor (physiology)
• Up-Regulation