Abstract
The tumor necrosis factor alpha receptor (TNFR1) activates downstream effectors that include the mitogen-activated protein kinase kinase 7 (MKK7)/c-Jun-NH(2)-kinase (JNK)/activator protein 1 (AP1) cascade. Here, we report that JNK is activated in a majority of spontaneous human squamous cell carcinomas (SCC). JNK pathway induction bypassed cell cycle restraints induced by oncogenic Ras and cooperated with Ras to convert normal human epidermis into tumors indistinguishable from SCC, confirming its oncogenic potency in human tissue. Inhibiting MKK7, JNK, and AP1 as well as TNFR1 itself using genetic, pharmacologic, or antibody-mediated approaches abolished invasive human epidermal neoplasia in a tumor cell autonomous fashion. The TNFR1/MKK7/JNK/AP1 cascade thus promotes human neoplasia and represents a potential therapeutic target for human epithelial cancers.
Highlights
Inflammation mediated by the cytokine tumor necrosis factor α (TNFα) and its receptor, TNFR1, is important in autoimmunity and has recently been implicated in neoplasia
Our findings show that the TNFR1/mitogen-activated protein kinase kinase 7 (MKK7)/Jun NH2-terminal kinases (JNK)/activator protein 1 (AP1) cascade promotes human neoplasia in a tumor cell– intrinsic manner and that its blockade at multiple levels abrogates tumorigenesis, indicating that targeted inhibition of this pathway represents a possible therapeutic approach for squamous cell carcinomas (SCC)
Tissues treated with SP600125 lacked invasive neoplasia and retained sharp delineation of the basement membrane zone (BMZ), with a humanspecific desmoglein-3 antibody confirming the human origin of these tissues (Fig. 2A). To confirm this pharmacologic finding, we studied the effects of inhibiting JNK cascade action through expression of the dominant-negative c-Jun TAM67 (DNc-Jun) that inhibits the function of AP1, the major target of JNK [7]
Summary
Inflammation mediated by the cytokine tumor necrosis factor α (TNFα) and its receptor, TNFR1, is important in autoimmunity and has recently been implicated in neoplasia. Both activator protein 1 (AP1) and nuclear factor-κB (NF-κB) family transcription factors are concomitantly activated by signals transmitted through TNFR1, via c-Jun NH2-terminal kinases (JNK) and IκB kinases (IKK), respectively [1,2]. Like NF-κB, AP1 subunits, which include Jun, Fos, activating transcription factor, and Fra family members, function as heterodimers or homodimers to regulate expression of a diverse array of genes. The immediate upstream activators of JNK are the mitogen-activated protein kinase (MAPK) kinases MKK4 and MKK7, with the latter displaying higher JNK specificity [4]
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