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: Ho-Jin Park, Su-Jin Lee, Young Bae Sohn, Hyun-Seok Jin, Jae-Ho Han, Young-Bae Kim, Hyunee Yim, Seon-Yong Jeong
• Journal: International journal of oncology (Int J Oncol) Vol. 42 Issue 2 Pg. 657-66 (Feb 2013) ISSN: 1791-2423 [Electronic] Greece
• PMID: 23292448 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ABT-737
• BCL2L1 protein, human
• Biphenyl Compounds
• Neurofibromin 1
• Nitrophenols
• Piperazines
• Sulfonamides
• bcl-X Protein
• Mitogen-Activated Protein Kinase Kinases
• ras Proteins

Topics

• Alleles
• Apoptosis (drug effects, genetics)
• Biphenyl Compounds (pharmacology)
• Cell Line, Tumor
• Gene Expression Regulation, Neoplastic (drug effects, genetics)
• Humans
• Mitogen-Activated Protein Kinase Kinases (metabolism)
• Nerve Sheath Neoplasms (complications, genetics, pathology)
• Neurofibromatosis 1 (complications, genetics, pathology)
• Neurofibromin 1 (deficiency, genetics)
• Nitrophenols (pharmacology)
• Piperazines (pharmacology)
• Schwann Cells (metabolism, pathology)
• Signal Transduction (drug effects)
• Sulfonamides (pharmacology)
• Up-Regulation
• bcl-X Protein (antagonists & inhibitors, genetics)
• ras Proteins (genetics, metabolism)