TGF-[beta] and NF-[kappa]B signal pathway cross-talk is mediated through TAK1 and SMAD7 in a subset of head and neck cancers

• Published in: Oncogene Vol. 32; no. 12; p. 1549
• Main Authors: Freudlsperger, C, Bian, Y, Contag Wise, S, Burnett, J, Coupar, J, Yang, X, Chen, Z, Van Waes, C
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group 21.03.2013
• Subjects: Gene expression; Head & neck cancer; Kinases; Oncology; Tumors
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2012.171

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-κB (NF-κB), a transcription factor, which promotes malignant progression in HNSCC. However, what role cross-talk between components of the TGF-[beta] and NF-κB 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-κB family member RELA (p65). Further, TGF-[beta]1 treatment induced sequential phosphorylation of TAK1, IKK, IκBα and RELA in human HNSCC lines. TAK1 enhances TGF-[beta]-induced NF-κB activation, as TAK1 siRNA knockdown decreased TGF-[beta]1-induced phosphorylation of IKK, IκB and RELA, degradation of IκBα, RELA nuclear translocation and DNA binding, and NF-κB-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-α)-induced NF-κB 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-κB reporters when compared with constitutive or TNF-α-induced NF-κB reporter gene activation. Thus, cross-talk by TGF-[beta] via TAK1 and NF-κB promotes the malignant phenotype of HNSCC. Moreover, NF-κB 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-κB signal pathway. [PUBLICATION ABSTRACT]