Bortezomib therapeutic effect is associated with expression and mutation of FGFR3 in human lymphoma cells.
OBJECTIVE
Ectopically expressed and deregulated fibroblast growth factor receptor 3 (FGFR3) has been observed in many malignant cancer patients, including those with lymphoma. This study investigated whether the therapeutic effect of bortezomib in lymphoma is associated with FGFR3-expression.


METHODS
Cell proliferation and apoptosis assays were performed in minimal FGFR3 expressing U937 cells and compared to U937 cells overexpressing FGFR3 wild-type, or Y373C or K650E mutant FGFR3.


RESULTS
Results from this study suggested the expression of FGFR3 protein is associated with the therapeutic effect of bortezomib. It was observed that bortezomib-induced apoptotic death is correlated with FGFR3 expression. U937 cells overexpression of wild-type FGFR3 demonstrated resistance to bortezomib treatment. U937 cells expressing Y373C mutated FGFR3 showed an almost equal resistance to bortezomib as U937 cells expressing wild-type FGFR3. U937 cells expressing mutated K650E FGFR3 showed more sensitivity to bortezomib than did the parental U937 cells. Furthermore, increased expression of Mcl-1 and decreased expression of NF-kappaB p65 suggested that bortezomib resistance associated with Y373C mutation and wild-type FGFR3 may be partly mediated through Bcl-2 and NF-kappaB signaling.


CONCLUSIONS
Data from this study indicate that mutation status and the expression level of FGFR3 may be associated with bortezomib-related treatment resistance in lymphoma.
Zheng
Weiyan
W
Department of Hematology, Bone Marrow Transplantation Center, First Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, Zhejiang, 310003, PR China.
Guan
Min
M
Zhu
Lijun
L
Cai
Zhen
Z
Chung
Vincent
V
Huang
He
H
Yen
Yun
Y
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy* / Q000235:genetics; D009154:Mutation; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016328:NF-kappa B / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D011719:Pyrazines / Q000494:pharmacology*; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics* / Q000502:physiology; D050794:STAT1 Transcription Factor / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000502:physiology; D020298:U937 Cells
D000970:Antineoplastic Agents; D001897:Boronic Acids; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D011719:Pyrazines; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000069286:Bortezomib; D051498:Receptor, Fibroblast Growth Factor, Type 3