TGF-β and NF-κB signal pathway cross-talk is mediated through TAK1 and SMAD7 in a subset of head and neck cancers

被引:240
作者
Freudlsperger, C. [1 ,2 ]
Bian, Y. [1 ]
Wise, S. Contag [1 ]
Burnett, J. [1 ]
Coupar, J. [1 ]
Yang, X. [1 ]
Chen, Z. [1 ]
Van Waes, C. [1 ]
机构
[1] Natl Inst Deafness & Other Commun Disorders, Tumor Biol Sect, Head & Neck Surg Branch, NIH, Bethesda, MD 20892 USA
[2] Univ Hosp Tuebingen, Dept Oral & Maxillofacial Surg, Tubingen, Germany
关键词
TGF-beta TAK1; NF-kappa B; SMAD7; celastrol; head and neck cancer; SQUAMOUS-CELL CARCINOMA; INDUCED APOPTOSIS; GENE-EXPRESSION; KINASE TAK1; GROWTH; ACTIVATION; RECEPTOR; PROTEIN; PROLIFERATION; INHIBITOR;
D O I
10.1038/onc.2012.171
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Transforming growth factor-beta (TGF-beta) has a dual role in epithelial malignancies, including head and neck squamous cell carcinoma (HNSCC). Attenuation of canonical TGF-beta signaling enhances de novo tumor development, whereas TGF-beta overexpression and signaling paradoxically promotes malignant progression. We recently observed that TGF-beta-induced growth arrest response is attenuated, in association with aberrant activation of nuclear factor-kappa B (NF-kappa B), a transcription factor, which promotes malignant progression in HNSCC. However, what role cross-talk between components of the TGF-beta and NF-kappa B pathways plays in altered activation of these pathways has not been established. Here, we show TGF-beta receptor II and TGF-beta-activated kinase 1 (TAK1) are predominantly expressed in a subset of HNSCC tumors with nuclear activation of NF-kappa B family member RELA (p65). Further, TGF-beta 1 treatment induced sequential phosphorylation of TAK1, IKK, I kappa B alpha and RELA in human HNSCC lines. TAK1 enhances TGF-beta-induced NF-kappa B activation, as TAK1 siRNA knockdown decreased TGF-beta 1-induced phosphorylation of IKK, I kappa B and RELA, degradation of I kappa B alpha, RELA nuclear translocation and DNA binding, and NF-kappa B-induced reporter and target gene transcription. Functionally, TAK1 siRNA inhibited cell proliferation, migration and invasion. Celastrol, a TAK1 inhibitor and anti-inflammatory compound used in traditional Chinese medicine, also decreased TGF-beta 1-induced phosphorylation of TAK1 and RELA, and suppressed basal, TGF-beta 1- and tumor necrosis factor-alpha (TNF-alpha)-induced NF-kappa B reporter gene activity. Celastrol also inhibited cell proliferation, while increasing sub-G0 DNA fragmentation and Annexin V markers of apoptosis. Furthermore, TGF-beta and RELA activation promoted SMAD7 expression. In turn, SMAD7 preferentially suppressed TGF-beta-induced SMAD and NF-kappa B reporters when compared with constitutive or TNF-alpha-induced NF-kappa B reporter gene activation. Thus, cross-talk by TGF-beta via TAK1 and NF-kappa B promotes the malignant phenotype of HNSCC. Moreover, NF-kappa B may contribute to the downstream attenuation of canonical TGF-beta signaling through increased SMAD7 expression. Celastrol highlights the therapeutic potential of agents targeting TAK1 as a key node in this pro-oncogenic TGF-beta-NF-kappa B signal pathway. Oncogene (2013) 32, 1549-1559; doi:10.1038/onc.2012.171; published online 28 May 2012
引用
收藏
页码:1549 / 1559
页数:11
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