Dissecting and targeting the growth factor-dependent and growth factor-independent extracellular signal-regulated kinase pathway in human schwannoma

被引:109
作者
Ammoun, Sylwia [1 ]
Flaiz, Christine [1 ]
Ristic, Natalia [1 ]
Schuldt, Jennifer [2 ]
Hanemann, C. Oliver [1 ]
机构
[1] Peninsula Coll Med & Dent, Plymouth PL6 8BU, Devon, England
[2] Univ Ulm, Dept Neurol, Zentrum Klin Forsch, D-7900 Ulm, Germany
关键词
D O I
10.1158/0008-5472.CAN-07-5849
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Schwannomas are tumors of the nervous system that occur sporadically and in patients with the cancer predisposition syndrome neurofibromatosis type 2 (NF2). Schwannomas and all NF2-related tumors are caused by loss of the tumor suppressor merlin. Using our human in vitro model for schwannoma, we analyzed extracellular signal-regulated kinase 1/2 (ERK1/2) and AKT signaling pathways, their upstream growth factor receptors, and their role in schwannoma cell proliferation and adhesion to find new systemic therapies for these tumors that, to date, are very difficult to treat. We show here that human primary schwannoma cells show an enhanced basal Raf/mitogen-activated protein/ERK kinase/ERK1/2 pathway activity compared with healthy Schwann cells. Due to a strong and prolonged activation of platelet-derived growth factor receptor beta (PDGFR beta), which is highly overexpressed, ERK1/2 and AKT activation was further increased in schwannoma, leading to increased proliferation. Using specific inhibitors, we discovered that ERK1/2 activation involves the integrin/focal adhesion kinase/Src/Ras signaling cascades and PDGFR beta-mediated ERK1/2 activation is triggered through the phosphatidylinositol 3-kinase/protein kinase C/Src/c-Raf pathway. Due to the complexity of signals leading to schwannoma cell proliferation, potential new therapeutic agents should target several signaling pathways. The PDGFR and c-Raf inhibitor sorafenib (BAY 43-9006; Bayer Pharmaceuticals), currently approved for treatment of advanced renal cell cancer, inhibits both basal and PDGFR beta-mediated ERK1/2 and AKT activity and decreases cell proliferation in human schwannoma cells, suggesting that this drug constitutes a promising tool to treat schwannomas. We conclude that our schwannoma in vitro model can be used to screen for new therapeutic targets in general and that sorafenib is possible candidate for future clinical trials.
引用
收藏
页码:5236 / 5245
页数:10
相关论文
共 53 条
  • [21] Mechanism of action and in vivo role of platelet-derived growth factor
    Heldin, CH
    Westermark, B
    [J]. PHYSIOLOGICAL REVIEWS, 1999, 79 (04) : 1283 - 1316
  • [22] A clue to the therapy of neurofibromatosis type 2: NF2/Merlin is a PAK1 inhibitor
    Hirokawa, Y
    Tikoo, A
    Huynh, J
    Utermark, T
    Hanemann, CO
    Giovannini, M
    Xiao, GH
    Testa, JR
    Wood, J
    Maruta, H
    [J]. CANCER JOURNAL, 2004, 10 (01) : 20 - 26
  • [23] Upregulation of the Rac1/JNK signaling pathway in primary human schwannoma cells
    Kaempchen, K
    Mielke, K
    Utermark, T
    Langmesser, S
    Hanemann, CO
    [J]. HUMAN MOLECULAR GENETICS, 2003, 12 (11) : 1211 - 1221
  • [24] Merlin, the product of the Nf2 tumor suppressor gene, the p21-activated is an inhibitor of kinase, Pak1
    Kissil, JL
    Wilker, EW
    Johnson, KC
    Eckman, MS
    Yaffe, MB
    Jacks, T
    [J]. MOLECULAR CELL, 2003, 12 (04) : 841 - 849
  • [25] Protein kinase C isotypes controlled by phosphoinositide 3-kinase through the protein kinase PDK1
    Le Good, JA
    Ziegler, WH
    Parekh, DB
    Alessi, DR
    Cohen, P
    Parker, PJ
    [J]. SCIENCE, 1998, 281 (5385) : 2042 - 2045
  • [26] Tyr-863 phosphorylation enhances focal adhesion kinase autophosphorylation at Tyr-397
    Leu, TH
    Maa, MC
    [J]. ONCOGENE, 2002, 21 (46) : 6992 - 7000
  • [27] Neuregulin signaling through a PI3K/Akt/Bad pathway in Schwann cell survival
    Li, YW
    Tennekoon, GI
    Birnbaum, M
    Marchionni, MA
    Rutkowski, JL
    [J]. MOLECULAR AND CELLULAR NEUROSCIENCE, 2001, 17 (04) : 761 - 767
  • [28] Merlin inhibits growth hormone-regulated Raf-ERKs pathways by binding to Grb2 protein
    Lim, JY
    Kim, H
    Jeun, SS
    Kang, SG
    Lee, KJ
    [J]. BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2006, 340 (04) : 1151 - 1157
  • [29] Membrane organization and tumorigenesis - the NF2 tumor suppressor, Merlin
    McClatchey, AI
    Giovannini, M
    [J]. GENES & DEVELOPMENT, 2005, 19 (19) : 2265 - 2277
  • [30] The Ras/Raf/MEK/ERK and PI3K/AKT signaling pathways present molecular targets for the effective treatment of advanced melanoma
    Meier, F
    Schittek, B
    Busch, S
    Garbe, C
    Smalley, K
    Satyamoorthy, K
    Li, G
    Herlyn, M
    [J]. FRONTIERS IN BIOSCIENCE-LANDMARK, 2005, 10 : 2986 - 3001