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

被引:12
作者
Park, Ho-Jin [1 ]
Lee, Su-Jin [1 ]
Sohn, Young Bae [1 ]
Jin, Hyun-Seok
Han, Jae-Ho [2 ]
Kim, Young-Bae [2 ]
Yim, Hyunee [2 ]
Jeong, Seon-Yong [1 ]
机构
[1] Ajou Univ, Dept Med Genet, Sch Med, Suwon 443721, South Korea
[2] Ajou Univ, Dept Pathol, Sch Med, Suwon 443721, South Korea
基金
新加坡国家研究基金会;
关键词
neurofibromatosis type 1; malignant peripheral nerve sheath tumor; Schwann cells; apoptosis; doxorubicin; ABT-737; ENHANCES CHEMOTHERAPY SENSITIVITY; MOLECULAR-MECHANISMS; PATHOGENESIS; BENIGN; GENE; TUMORIGENESIS; BCL-X(L); MUTATION; PROTEIN; FAMILY;
D O I
10.3892/ijo.2012.1751
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
收藏
页码:657 / 666
页数:10
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