Gene expression profiling and bioinformatic analysis of the promoters of gene clusters differentially expressed in HNSCC provided evidence for increased prevalence of binding motifs for signal transcription factors p53, nuclear factor-kappaB, AP-1, STAT3 and EGR-1 (Yan et al, Genome Biology, 2007). An NF-kappaB gene signature was found to be differentially expressed in relation to wild type or mutant genotype status of p53, an important tumor suppressor gene in HNSCC and other cancer (Lee et al, Clin Cancer Res, 2007). NF-kappaB activation is associated with therapeutic resistance, and the subsets expressing wt or mt 53 have been reported to differ in response to chemotherapy in clinical trials.? ? During the present period, we reported that in the subset of HNSCC expressing the NF-kappaB gene signature, there is deficient expression of wt p53 mRNA and protein, and resistance of wt p53 to induction by doxorubicin and cisplatin, DNA damaging chemotherapy agents that are known inducers of p53 (1). These findings suggested that a common mechanism may be responsible activating NF-kappaB and inactivating p53 in this subset. We demonstrated that the anti-malarial and inflammatory drug quinacrine can restore p53 expression, function and cisplatin sensitivity of HNSCC. Quinacrine may hold potential alone and in combination with DNA damaging agents for therapy.? ? We next reported that a signal network involving co-activated NF-kappaB and STAT3 and altered p53 modulate expression of cell life and death genes BCL-XL and BAX, promoting survival of HNSCC (2). Greater modulation among HNSCC lines expressing low wt p53 than those over-expressing mt p53 protein suggested that decreased p53 expression might enhance activation of NF-kappaB, STAT3 and BCL-XL. Reexpression of wt p53 suppressed NF-kappaB and STAT3 nuclear binding activity, and BCL-XL expression, while inducing p21 and BAX. Over-expression of p53 together with inhibition of NF-kappaB or STAT3 induced greater increase in the BAX/BCL-XL ratio and apoptosis than modulation of these transcription factors individually. Conversely, NF-kappaB or STAT3 inducing cytokines decreased the BAX/BCL-XL ratio. Thus, a network involving signal coactivation of NF-kappaB and STAT3, differentially modified by p53 inactivation or mutation, promotes altered BAX/BCL-XL expression and cell survival in HNSCC. Inhibition of signal activation of both NF-kappaB and STAT3 together with reexpression of p53 could be the most effective strategy to restore BAX/BCL-XL regulation and for cytotoxic therapy of HNSCC.? ? In collaboration with King, Weinberg and colleagues in the FDA, who found that the p53 homologue DeltaNp63alpha interacts with the nuclear factor-kappaB pathway to modulate epithelial cell growth, we demonstrated that DeltaNp63alpha and cREL are constitutively activated and form a novel transcription factor complex and interaction between the NF-kappaB and p53 families (3). DeltaNp63alpha-c-Rel complexes bound a promoter motif and repressed the cyclin-dependent kinase inhibitor p21WAF1 in both human squamous carcinoma cells and normal keratinocytes overexpressing DeltaNp63alpha. The relationship between DeltaNp63alpha and activated c-Rel was reflected in their strong nuclear staining in the proliferating compartment of primary HNSCC. This is the first report indicating that high levels of DeltaNp63alpha interact with activated c-Rel in keratinocytes and HNSCC, thereby promoting uncontrolled proliferation, a key alteration in the pathogenesis of cancers.? ? In our ongoing clinical trial of proteasome inhibitor bortezomib with re-irradiation, we observed apoptosis and limited clinical activity with inhibition of NF-kappaB, but found that ERK1/2-AP-1 and STAT3 pathways were not inhibited, consistent with the possibility that these pathways contribute to survival and resistance of HNSCC (Allen et al, Clin Cancer Res, 2008). Study of the possible role of these alterations in differential bortezomib sensitivity in head and neck cancer lines provided evidence for proteasome, NF-kappaB and AP-1 related mechanisms (4). Inhibition of c-Jun NH(2)-terminal kinase and p38 pathways blocked AP-1 activity and enhanced the antitumor effects. These findings revealed molecular mechanisms of bortezomib sensitivity and resistance, which are under development as biomarkers for clinical research trials in patients with head and neck cancer.? ? Based on our findings that inhibitors of the Epidermal Growth Factor Receptor and NF-kappaB differentially affect activation of the ERK-AP-1, NF-kappaB and STAT3 pathways (Bancroft Int J Cancer, 2002; Allen, Clin Cancer Res, 2008; and ref. 4), we have initiated a phase I clinical research trial combining bortezomib with EGFR inhibitor cetuximab, without or with cisplatin and radiation for patients with stage IV HNSCC. Because these pathways are important in development of head and neck cancer, investigation of natural and synthetic products that target these pathways for cancer prevention are warranted.
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