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

Abstract

TGF-β plays a dual role in epithelial malignancies, including head and neck squamous cell carcinoma (HNSCC). Attenuation of canonical TGF-β signaling enhances de novo tumor development, while TGF-β overexpression and signaling paradoxically promotes malignant progression. We recently observed that TGF-β-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-β and NF-κB pathways plays in altered activation of these pathways has not been established. Here, we show TGF-β receptor II and TGF-β-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-β1 treatment induced sequential phosphorylation of TAK1, IKK, IκBα, and RELA in human HNSCC lines. TAK1 enhances TGF-β-induced NF-κB activation, as TAK1 siRNA knock-down decreased TGF-β1-induced phosphorylation of IKK, IκB, and RELA, degradation of IκBα, nuclear translocation, and DNA binding of RELA, 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 used in traditional Chinese medicine, also decreased TGF-β1-induced phosphorylation of TAK1 and RELA, suppressed basal, TGF-β1- and TNFα-induced NF-κB reporter gene activity, and cell proliferation, while increasing sub-G0 DNA fragmentation and Annexin V markers of apoptosis. Furthermore, TGF-β and RELA activation promoted SMAD7 expression. In turn, SMAD7 preferentially suppressed TGF-β-induced SMAD and NF-κB reporters when compared with constitutive or TNF-α-induced NF-κB reporter gene activation. Thus, cross-talk by TGF-β via TAK1 and NF-κB promotes the malignant phenotype of HNSCC. Moreover, NF-κB may contribute to the downstream attenuation of canonical TGF-β signaling through increased SMAD7 expression. Celastrol highlights the therapeutic potential of agents targeting TAK1 as a key node in this pro-oncogenic TGF-β-NF-κB signal pathway.

RETRACTED: Minocycline Targets the NF-κB Nexus through Suppression of TGF-β1-TAK1-IκB Signaling in Ovarian Cancer

“…On the basis of these data, it has been suggested that in the context of ovarian cancer, mutations and/or alterations of the key nodes along canonical TGF-b pathway shift TGF-b to noncanonical pathways such as activation of NF-kB which describes the pro-oncogenic role of TGF-b in advanced ovarian cancer (38,39). In fact, activation of TGF-b/NFkB pathway has been defined as the underlying mechanism in the phenomenon of conversion of TGF-b from a tumor suppressor to a tumor promoter during tumorigenesis (28,40,41). In our study, it was found that minocycline downregulates the endogenous levels of TGF-b1.…”

Extracellular acidity strengthens mesenchymal stem cells to promote melanoma progression

“…46 Numerous reports underlined that through TGFb secretion MSC promote a malignant phenotype in tumor cells of different histotype 10,21 The higher level of TGFb secreted by acidic MSC does not prevent proliferation of LpH-MSC-adapted melanoma cells, a condition that might be related to SMAD/NF-kB signaling interplays, as suggested by Freudlsperger et al's findings in head and neck cancers. 32 We also found that esomeprazole, a proton pump inhibitor activated by acidic medium, inhibits TGFb of acidic MSC, which corresponds to a MET program in melanoma cells grown in LpH-esomeprazole-treated MSC medium. These cells were characterized by a reduction of N-cadherin, TGFb, invasiveness and motility, and elevation of E-cadherin.…”

“…28 NF-kB and melanoma progression is reviewed by Amiri and Richmond. 29 Elevation of NF-kB expression in melanoma cells grown in LpH-MSC medium is potentially involved in several aspects of the acquired phenotype, such as stabilization of Snail transcription factor, 30 loss of E-Cadherin expression, 31 attenuation of TGFb-induced inhibition of proliferation 32 and, finally, metabolism. 33 Thereafter, these cells express an increased motility and invasiveness after suspension in MMP-enriched LpH-MSC medium.…”

Oxidative stress mediates the conversion of endothelial cells into myofibroblasts via a TGF-β1 and TGF-β2-dependent pathway

“…73,74 Thus, it would be interesting to test whether H 2 O 2 -induced conversion of ECs into myofibroblasts is inhibited by a p38 MAPK inhibitor; however, further experiments are needed to test this idea. Although NF-kB activity is normally suppressed by TGF-b in normal cells, NF-kB can be activated upon TGF-b treatment in pathological cells, 25,26,75,76 which could be the mechanism for H 2 O 2 -induced conversion of ECs into myofibroblasts.…”

“…23,24 Several proteins that are involved in TGF-b intracellular signaling include the canonical pathway of phosphorylation of the family of Smad proteins and non-canonical intracellular pathways, to perform the activation of nuclear factor-kappa B (NF-kB). [24][25][26][27][28] Specifically, the Smad3 protein emerges as a pro-fibrotic member of the Smad protein family because its phosphorylation promotes the progression of fibrosis. 29,30 It has been reported that oxidative stress induces the EMT.…”