Sorafenib inhibits growth and mitogen-activated protein kinase signaling in malignant peripheral nerve sheath cells Journal Article
| Authors: | Ambrosini, G.; Cheema, H. S.; Seelman, S.; Teed, A.; Sambol, E. B.; Singer, S.; Schwartz, G. K. |
| Article Title: | Sorafenib inhibits growth and mitogen-activated protein kinase signaling in malignant peripheral nerve sheath cells |
| Abstract: | Malignant peripheral nerve sheath tumors (MPNST) are soft-tissue tumors with a very poor prognosis and largely resistant to chemotherapy. MPNSTs are characterized by activation of the Ras pathway by loss of tumor suppressor neurofibromatosis type 1. In view of this, MPNST may be susceptible to inhibition of the activated Ras/Raf/mitogen-activated protein kinase pathway by the B-Raf inhibitor sorafenib. MPNST (MPNST and ST8814) and dedifferentiated liposarcoma (LS141 and DDLS) human tumor cell lines were characterized for Ras activation and B-Raf expression. Tumor cells were treated with sorafenib and examined for growth inhibition, inhibition of phospho-MEK, phospho-ERK, cell cycle arrest, and changes in cyclin D1 and pRb expression. MPNSTs were sensitive to sorafenib at nanomolar concentrations. This appeared to be due to inhibition of phospho-MEK, phospho-ERK, suppression of cyclin D1, and hypophosphorylation of pRb at the CDK4-specific sites, resulting in a G1 cell cycle arrest. These effects were not seen in the liposarcoma cells, which either did not express B-Raf or showed decreased Ras activation. Small interfering RNA-mediated depletion of B-Raf in MPNSTs also induced a G1 cell cycle arrest in these cells, with a marked inhibition of cyclin D1 expression and Rb phosphorylation, whereas depletion of C-Raf did not affect either. With growth inhibition at the low nanomolar range, sorafenib, by inhibiting the mitogen-activated protein kinase pathway, may prove to be a novel therapy for patients with MPNST. Copyright © 2008 American Association for Cancer Research. |
| Keywords: | signal transduction; mitogen activated protein kinase; protein expression; protein phosphorylation; human cell; sorafenib; raf protein; antineoplastic agents; benzenesulfonates; pyridines; flow cytometry; cell proliferation; apoptosis; small interfering rna; cell differentiation; cancer cell culture; enzyme activation; enzyme activity; phosphorylation; cancer inhibition; blotting, western; extracellular signal-regulated map kinases; cell cycle arrest; ras protein; gene silencing; ras proteins; tumor growth; cyclin d1; mitogen-activated protein kinases; retinoblastoma protein; nerve sheath tumor; nerve sheath neoplasms; b raf kinase; mitogen-activated protein kinase kinases; g1 phase; proto-oncogene proteins b-raf; liposarcoma; cyclin-dependent kinase 4; proto-oncogene proteins c-raf |
| Journal Title: | Molecular Cancer Therapeutics |
| Volume: | 7 |
| Issue: | 4 |
| ISSN: | 1535-7163 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2008-04-01 |
| Start Page: | 890 |
| End Page: | 896 |
| Language: | English |
| DOI: | 10.1158/1535-7163.mct-07-0518 |
| PUBMED: | 18413802 |
| PROVIDER: | scopus |
| PMCID: | PMC3267321 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 16" - "Export Date: 17 November 2011" - "CODEN: MCTOC" - "Source: Scopus" |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work