title: A novel role for BDNF-TrkB in the regulation of chemotherapy resistance in head and neck squamous cell carcinoma.
abstract: Mechanisms of resistance for HNSCC to cisplatin (CDDP), the foundational chemotherapeutic agent in the treatment of this disease, remain poorly understood. We previously demonstrated that cisplatin resistance (CR) can be overcome by targeting Trk receptor. In the current study, we explored the potential mechanistic role of the BDNF-TrkB signaling system in the development of CDDP resistance in HNSCC. Utilizing an in vitro system of acquired CR, we confirmed a substantial up-regulation of both BDNF and TrkB at the protein and mRNA levels in CR cells, suggesting an autocrine pathway dysregulation in this system. Exogenous BDNF stimulation led to an enhanced expression of the drug-resistance and anti-apoptotic proteins MDR1 and XiAP, respectively, in a dose-dependently manner, demonstrating a key role for BDNF-TrkB signaling in modulating the response to cytotoxic agents. In addition, modulation of TrkB expression induced an enhanced sensitivity of cells to CDDP in HNSCC. Moreover, genetic suppression of TrkB resulted in changes in expression of Bim, XiAP, and MDR1 contributing to HNSCC survival. To elucidate intracellular signaling pathways responsible for mechanisms underlying BDNF/TrkB induced CDDP-resistance, we analyzed expression levels of these molecules following inhibition of Akt. Inhibition of Akt eliminated BDNF effect on MDR1 and Bim expression in OSC-19P cells as well as modulated expressions of MDR1, Bim, and XiAP in OSC-19CR cells. These results suggest BDNF/TrkB system plays critical roles in CDDP-resistance development by utilizing Akt-dependent signaling pathways.
authors.affiliation: Department of Head and Neck Surgery, MD Anderson Cancer Center, University of Texas, Houston, Texas, United States of America.
authors.forename: Junegoo
authors.initials: J
authors.lastname: Lee
authors.forename: Tilahun
authors.initials: T
authors.lastname: Jiffar
authors.forename: Michael E
authors.initials: ME
authors.lastname: Kupferman
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D015153:Blotting, Western; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D006258:Head and Neck Neoplasms / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077195:Squamous Cell Carcinoma of Head and Neck; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D019208:Brain-Derived Neurotrophic Factor; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D020813:Receptor, trkB; D002945:Cisplatin