[Study of brain-derived neurotrophic factor activating TrkB signaling cascades in the pathogenesis of multiple myeloma].
OBJECTIVE
To explore the significance of abnormal expression of brain-derived neurotrophic factor (BDNF)/TrkB in the development and evolution of multiple myeloma (MM) and the involved signaling pathways.


METHODS
The effect of BDNF on the cell viability of human myeloma cell line (HMCL) (RPMI8226, U266, KM3) was determined by trypan blue dye-exclusion. MTT assay was used to evaluate the cytotoxicity of tested chemotherapeutic agents. The effect of BDNF on the phosphorylation of TrkB was determined by Western blot. A human myeloma xenograft animal model was used to evaluate the effects of BDNF on tumor growth and survival time.


RESULTS
BDNF at 50 microg/L triggered significant increase in cell viability of HMCL. BDNF protected KM3 cells from melphalan and vincristine. The viability of KM3 cells exposed to varying concentrations of melphalan with and without 50 microg/L BDNF showed that BDNF induced almost a 2-fold and a 3-fold increase in melphalan and vincristine toxicity respectively. BDNF treatment increased MM cell growth in xenografted MM model (3240.9 mm3 vs 1032.7 mm3 ) (P <0.05). Intratumoral injection of BDNF also significantly reduced survival time (13 d vs 21 d) (P <0.05). The phosphorylated TrkB level was increased significantly after treated by exogenous BDNF. BDNF-triggered migration in RPMI8226 cells was completely abrogated by a Trk tyrosine kinase inhibitor K252a.


CONCLUSIONS
BDNF can activate TrkB signaling cascades resulting in MM cells growth, migration, and chemoprotection and appears to have a major contribution to the pathogenesis of MM.
Sun
Chun-Yan
CY
Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Hu
Yu
Y
Guo
Tao
T
Huang
Jing
J
Zhang
Lu
L
Chu
Zhang-Bo
ZB
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D020813:Receptor, trkB / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D019208:Brain-Derived Neurotrophic Factor; D020813:Receptor, trkB