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

  • Authors:
    • Ho-Jin Park
    • Su-Jin Lee
    • Young Bae Sohn
    • Hyun-Seok Jin
    • Jae‑Ho Han
    • Young-Bae Kim
    • Hyunee Yim
    • Seon-Yong Jeong
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  • Published online on: December 24, 2012     https://doi.org/10.3892/ijo.2012.1751
  • Pages: 657-666
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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.
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February 2013
Volume 42 Issue 2

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APA
Park, H., Lee, S., Sohn, Y., Jin, H., Han, J., Kim, Y. ... Jeong, S. (2013). NF1 deficiency causes Bcl-xL upregulation in Schwann cells derived from neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors. International Journal of Oncology, 42, 657-666. https://doi.org/10.3892/ijo.2012.1751
MLA
Park, H., Lee, S., Sohn, Y., Jin, H., Han, J., Kim, Y., Yim, H., Jeong, S."NF1 deficiency causes Bcl-xL upregulation in Schwann cells derived from neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors". International Journal of Oncology 42.2 (2013): 657-666.
Chicago
Park, H., Lee, S., Sohn, Y., Jin, H., Han, J., Kim, Y., Yim, H., Jeong, S."NF1 deficiency causes Bcl-xL upregulation in Schwann cells derived from neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors". International Journal of Oncology 42, no. 2 (2013): 657-666. https://doi.org/10.3892/ijo.2012.1751