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题名:Evidence that TNF-TNFR1-TRADD-TRAF2-RIP-TAK1-IKK pathway mediates constitutive NF-kappaB activation and proliferation in human head and neck squamous cell carcinoma.
作者:Jackson-Bernitsas DG, Ichikawa H, Takada Y, Myers JN, Lin XL, Darnay BG, Chaturvedi MM, Aggarwal BB.
来源:Oncogene[IF=6.872]. 2007 Mar 1;26(10):1385-97. Epub 2006 Sep 4.
URL :http://dx.doi.org/10.1038/sj.onc.1209945
日期:070415
摘要: D G Jackson-Bernitsas1, H Ichikawa1, Y Takada1, J N Myers2, X L Lin3, B G Darnay1, M M Chaturvedi1,4 and B B Aggarwal1

1Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
2Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
3Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Correspondence: Professor BB Aggarwal, Cytokine Research Laboratory, Department of Experimental Therapeutics, Unit 143, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. E-mail: aggarwal@mdanderson.org

4On leave from the Department of Zoology, University of Delhi, Delhi 110007, India

Received 2 May 2006; Revised 18 July 2006; Accepted 21 July 2006; Published online 4 September 2006.

Abstract

Constitutively activated nuclear factor-B (NF-B) has been associated with a variety of aggressive tumor types, including head and neck squamous cell carcinoma (HNSCC); however, the mechanism of its activation is not fully understood. Therefore, we investigated the molecular pathway that mediates constitutive activation of NF-B in a series of HNSCC cell lines. We confirmed that NF-B was constitutively active in all HNSCC cell lines (FaDu, LICR-LON-HN5 and SCC4) examined as indicated by DNA binding, immunocytochemical localization of p65, by NF-B-dependent reporter gene expression and its inhibition by dominant-negative (DN)-inhibitory subunit of NF-B (IB), the natural inhibitor of NF-B. Constitutive NF-B activation in HNSCC was found to be due to constitutive activation of IB kinase (IKK); and this correlated with constitutive expression of phosphorylated forms of IB and p65 proteins. All HNSCC showed the expression of p50, p52, p100 and receptor-interacting protein; all linked with NF-B activation. The expression of constitutively active NF-B in HNSCC is mediated through the tumor necrosis factor (TNF) signaling pathway, as NF-B reporter activity was inhibited by DN-TNF receptor-associated death domain (TRADD), DN-TNF receptor-associated factor (TRAF)2, DN-receptor-interacting protein (RIP), DN-transforming growth factor--activated kinase 1 (TAK1), DN--Ras, DN-AKT and DN-IKK but not by DN-TRAF5 or DN-TRAF6. Constitutive NF-B activation was also associated with the autocrine expression of TNF, TNF receptors and receptor-activator of NF-B and its ligand in HNSCC cells but not interleukin (IL)-1. All HNSCC cell lines expressed IL-6, a NF-B-regulated gene product. Furthermore, treatment of HNSCC cells with anti-TNF antibody downregulated constitutively active NF-B, and this was associated with inhibition of IL-6 expression and cell proliferation. Our results clearly demonstrate that constitutive activation of NF-B is mediated through the TRADD-TRAF2-RIP-TAK1-IKK pathway, making TNF a novel target in the treatment of head and neck cancer.

Keywords: head and neck squamous cell carcinoma, nuclear factor-B, tumor necrosis factor, proliferation

Abbreviations: ALLN, N-acetyl-leu-leu-norleucinal; IB, inhibitory subunit of NF-B; IKK, IB kinase; JNK, c-Jun N terminal kinase; MAPK, mitogen-activated protein kinase; MEKK, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase; NF-B, nuclear factor-B; PBS, phosphate-buffered saline; TRAF, TNF receptor-associated factor; RANK, receptor activator of NF-B; RANKL, receptor activator of NF-B ligand; TNF, tumor necrosis factor; TRADD, TNF receptor-associated death domain; RIP, receptor-interacting protein; TAK1, transforming growth factor--activated kinase 1; TAB1, TAK1-binding protei

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