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NF1 deficiency causes Bcl-xL upregulation in Schwann cells derived from neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors.

Authors
Park, HJ; Lee, SJ; Sohn, YB; Jin, HS; Han, JH; Kim, YB; Yim, H; Jeong, SY
Citation
International journal of oncology, 42(2):657-666, 2013
Journal Title
International journal of oncology
ISSN
1019-64391791-2423
Abstract
Since the bi-allelic inactivation of both neurofibromin 1 (NF1) gene alleles (NF1(-/-)) in Schwann cells (SCs) is common in both benign plexiform neurofibromas (PNs) and malignant peripheral nerve sheath tumors (MPNSTs) in patients with neurofibromatosis type 1 (NF1), other genetic alterations in SCs may be required for tumor progression of PNs to MPNSTs. We found that the anti-apoptotic Bcl-xL protein is upregulated in MPNST tissues compared to PN tissues from patients with NF1 by immunohistological staining. In addition, we investigated whether Bcl-xL is upregulated in SCs derived from MPNSTs and found a significantly higher Bcl-xL expression level in sNF96.2 MPNST-derived SCs compared to normal human SCs (HSCs). We also discovered that the increased Bcl-xL expression caused an increase in drug resistance to doxorubicin in MPNST-derived SCs. Manipulation of NF1 gene expression levels by treatment with small interfering RNA (siRNA) and overexpression of the neurofibromin GAP-related domain (NF1-GRD) demonstrated that upregulated Bcl-xL expression in MPNST-derived SCs was caused by NF1 deficiency. Treatment with the Erk1/2 inhibitor, PD98059, resulted in a slight increase in Bcl-xL levels in neurofibromin-depleted normal HSCs, indicating that Bcl-xL upregulation in MPNST-derived SCs is mediated by activated Erk1/2, which is a Ras downstream protein regulated by neurofibromin. As the reduction of Bcl-xL expression restored sensitivity to doxorubicin-induced apoptosis in sNF96.2 cells, we examined the effect of the small molecule Bcl-xL inhibitor ABT-737 on sNF96.2 cells. A very low dose of ABT-737 combined with doxorubicin synergistically enhanced sensitivity to doxorubicin-induced apoptosis in sNF96.2 cells, suggesting that ABT-737 and doxorubicin may be a good combination to effectively treat NF1-associated MPNSTs with minimal side-effects. Collectively, our results suggest that upregulation of Bcl-xL in MPNST-derived SCs may be caused by the NF1 deficiency-mediated elevation in Ras/MAPK signaling and may provide a new potential chemotherapeutic target in patients with NF1 and MPNSTs.
MeSH terms
AllelesApoptosis/drug effects/geneticsBiphenyl Compounds/pharmacologyCell Line, TumorGene Expression Regulation, Neoplastic/drug effects/geneticsHumansMitogen-Activated Protein Kinase Kinases/metabolismNerve Sheath Neoplasms/complications/*genetics/pathologyNeurofibromin 1/deficiency/*geneticsNitrophenols/pharmacologyPiperazines/pharmacologySchwann Cells/metabolism/pathologySignal Transduction/drug effectsSulfonamides/pharmacologyUp-Regulationbcl-X Protein/antagonists & inhibitors/*geneticsras Proteins/genetics/metabolism
DOI
10.3892/ijo.2012.1751
PMID
23292448
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Medical Genetics
Journal Papers > School of Medicine / Graduate School of Medicine > Pathology
AJOU Authors
손, 영배진, 현석한, 재호김, 영배임, 현이정, 선용
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