Protein kinase B modulates the sensitivity of human neuroblastoma cells to insulin‐like growth factor receptor inhibition

International Journal of Cancer - Tập 119 Số 11 - Trang 2527-2538 - 2006
Ana Guerreiro Stücklin1, Danielle Boller1, Tarek Shalaby2, Michael Grotzer2, Alexandre Arcaro1
1Division of Clinical Chemistry and Biochemistry, University Children’s Hospital Zurich, CH-8032 Zurich, Switzerland
2Department of Oncology, University Children's Hospital Zurich, CH‐8032 Zurich, Switzerland

Tóm tắt

AbstractThe potential of the novel insulin‐like growth factor receptor (IGF‐IR) inhibitor NVP‐AEW541 as an antiproliferative agent in human neuroblastoma was investigated. Proliferation of a panel of neuroblastoma cell lines was inhibited by NVP‐AEW541 with IC50 values ranging from 0.15 to 5 μM. Experiments using an IGF‐IR neutralizing antibody confirmed that the IGF‐IR was essential to support growth of neuroblastoma cell lines. The expression levels of the IGF‐IR in individual neuroblastoma cell lines did not correlate with the sensitivities to NVP‐AEW541, while coexpression of the IGF‐IR and the insulin receptor (IR) correlated with lower sensitivity to the inhibitor in some cell lines. Intriguingly, high levels of activation of Akt/protein kinase B (PKB) and phosphorylation of the ribosomal S6 protein were observed in neuroblastoma cell lines with decreased sensitivities to NVP‐AEW541. Inhibition of Akt/PKB activity restored the sensitivity of neuroblastoma cells to the IGF‐IR inhibitor. Transfection of neuroblastoma cells with activated Akt or ribosomal protein S6 kinase (S6K) decreased the sensitivity of the cells to NVP‐AEW541. IGF‐I‐stimulated proliferation of neuroblastoma cell lines was completely blocked by NVP‐AEW541, or by a combination of an inhibitor of phosphoinositide 3‐kinase and rapamycin. In addition to its antiproliferative effects, NVP‐AEW541 sensitized neuroblastoma cells to cisplatin‐induced apoptosis. Together, our data demonstrate that NVP‐AEW541 in combination with Akt/PKB inhibitors or chemotherapeutic agents may represent a novel approach to target human neuroblastoma cell proliferation. © 2006 Wiley‐Liss, Inc.

Từ khóa


Tài liệu tham khảo

10.1053/jpdn.2003.12

10.1016/S1470-2045(03)01166-5

10.1056/NEJM199910143411601

10.1038/sj.onc.1204927

Singleton JR, 1996, Insulin‐like growth factor I receptor prevents apoptosis and enhances neuroblastoma tumorigenesis, Cancer Res, 56, 4522

10.1006/excr.1995.1365

10.1172/JCI115042

10.1007/s004310050595

10.1093/jnci/djh004

Ho R, 2002, Resistance to chemotherapy mediated by TrkB in neuroblastomas, Cancer Res, 62, 6462

Stefanik DF, 1991, Acidic and basic fibroblast growth factors are present in glioblastoma multiforme, Cancer Res, 51, 5760

10.1002/jnr.490360211

10.1073/pnas.140210697

10.1182/blood.V84.10.3465.3465

10.1146/annurev.biochem.70.1.535

10.1002/bies.10031

10.1073/pnas.96.8.4240

10.1016/j.ccr.2004.11.004

Jaboin J, 2002, Brain‐derived neurotrophic factor activation of TrkB protects neuroblastoma cells from chemotherapy‐induced apoptosis via phosphatidylinositol 3′‐kinase pathway, Cancer Res, 62, 6756

10.1038/sj.onc.1206924

10.1016/S1535-6108(04)00051-0

10.1128/MCB.23.3.852-863.2003

10.1038/nature03095

10.1126/science.1099314

10.1126/science.1101637

Maloney EK, 2003, An anti‐insulin‐like growth factor I receptor antibody that is a potent inhibitor of cancer cell proliferation, Cancer Res, 63, 5073

Warshamana‐Greene GS, 2004, The insulin‐like growth factor‐I (IGF‐I) receptor kinase inhibitor NVP‐ADW742, in combination with STI571, delineates a spectrum of dependence of small cell lung cancer on IGF‐I and stem cell factor signaling, Mol Cancer Ther, 3, 527, 10.1158/1535-7163.527.3.5

10.1093/jnci/djh217

10.1158/1078-0432.CCR-04-1544

Thông tin
Thông tin xuất bản

International Journal of Cancer

Tập 119 Số 11

2527-2538

Thông tin tác giả