title: NF1 deficiency causes Bcl-xL upregulation in Schwann cells derived from             neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors.
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.
authors.affiliation: Department of Medical Genetics, Ajou University School of Medicine,                     Suwon 443-721, Republic of Korea.
authors.forename: Ho-Jin
authors.initials: HJ
authors.lastname: Park
authors.forename: Su-Jin
authors.initials: SJ
authors.lastname: Lee
authors.forename: Young Bae
authors.initials: YB
authors.lastname: Sohn
authors.forename: Hyun-Seok
authors.initials: HS
authors.lastname: Jin
authors.forename: Jae-Ho
authors.initials: JH
authors.lastname: Han
authors.forename: Young-Bae
authors.initials: YB
authors.lastname: Kim
authors.forename: Hyunee
authors.initials: H
authors.lastname: Yim
authors.forename: Seon-Yong
authors.initials: SY
authors.lastname: Jeong
mesh_terms: D000483:Alleles; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001713:Biphenyl Compounds / Q000494:pharmacology; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D018317:Nerve Sheath Neoplasms / Q000150:complications / Q000235:genetics* / Q000473:pathology; D009456:Neurofibromatosis 1 / Q000150:complications / Q000235:genetics* / Q000473:pathology; D025542:Neurofibromin 1 / Q000172:deficiency / Q000235:genetics*; D009596:Nitrophenols / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D012583:Schwann Cells / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology; D015854:Up-Regulation; D051020:bcl-X Protein / Q000037:antagonists & inhibitors / Q000235:genetics*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C501332:ABT-737; C494811:BCL2L1 protein, human; D001713:Biphenyl Compounds; D025542:Neurofibromin 1; D009596:Nitrophenols; D010879:Piperazines; D013449:Sulfonamides; D051020:bcl-X Protein; D020929:Mitogen-Activated Protein Kinase Kinases; D018631:ras Proteins