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

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dc.contributor.authorPark, HJ-
dc.contributor.authorLee, SJ-
dc.contributor.authorSohn, YB-
dc.contributor.authorJin, HS-
dc.contributor.authorHan, JH-
dc.contributor.authorKim, YB-
dc.contributor.authorYim, H-
dc.contributor.authorJeong, SY-
dc.date.accessioned2014-05-02T04:39:13Z-
dc.date.available2014-05-02T04:39:13Z-
dc.date.issued2013-
dc.identifier.issn1019-6439-
dc.identifier.urihttp://repository.ajou.ac.kr/handle/201003/9884-
dc.description.abstractSince 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.-
dc.language.isoen-
dc.subject.MESHAlleles-
dc.subject.MESHApoptosis-
dc.subject.MESHBiphenyl Compounds-
dc.subject.MESHCell Line, Tumor-
dc.subject.MESHGene Expression Regulation, Neoplastic-
dc.subject.MESHHumans-
dc.subject.MESHMitogen-Activated Protein Kinase Kinases-
dc.subject.MESHNerve Sheath Neoplasms-
dc.subject.MESHNeurofibromin 1-
dc.subject.MESHNitrophenols-
dc.subject.MESHPiperazines-
dc.subject.MESHSchwann Cells-
dc.subject.MESHSignal Transduction-
dc.subject.MESHSulfonamides-
dc.subject.MESHUp-Regulation-
dc.subject.MESHbcl-X Protein-
dc.subject.MESHras Proteins-
dc.titleNF1 deficiency causes Bcl-xL upregulation in Schwann cells derived from neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors.-
dc.typeArticle-
dc.identifier.pmid23292448-
dc.identifier.urlhttp://www.spandidos-publications.com/ijo/42/2/657-
dc.contributor.affiliatedAuthor손, 영배-
dc.contributor.affiliatedAuthor진, 현석-
dc.contributor.affiliatedAuthor한, 재호-
dc.contributor.affiliatedAuthor김, 영배-
dc.contributor.affiliatedAuthor임, 현이-
dc.contributor.affiliatedAuthor정, 선용-
dc.type.localJournal Papers-
dc.identifier.doi10.3892/ijo.2012.1751-
dc.citation.titleInternational journal of oncology-
dc.citation.volume42-
dc.citation.number2-
dc.citation.date2013-
dc.citation.startPage657-
dc.citation.endPage666-
dc.identifier.bibliographicCitationInternational journal of oncology, 42(2). : 657-666, 2013-
dc.identifier.eissn1791-2423-
dc.relation.journalidJ010196439-
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Medical Genetics
Journal Papers > School of Medicine / Graduate School of Medicine > Pathology
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