title: A signal network involving coactivated NF-kappaB and STAT3 and altered p53 modulates BAX/BCL-XL expression and promotes cell survival of head and neck squamous cell carcinomas.
abstract: Abrogation of apoptosis to sustain cell survival is an essential step in development of cancer. Aberrant activation of signal transcription factors NF-kappaB or STAT3, alterations in p53 status, or BCL/BAX family expression have each been reported to affect cell survival in cancer, including head and neck squamous cell carcinomas (HNSCC). However, molecular targeting of these alterations individually has yielded disappointing results. In our study, we examined the hypothesis that alterations in a signal network involving NF-kappaB, STAT3 and p53 modulates expression of proapoptotic BAX and antiapoptotic BCL-XL proteins, and promotes cell survival of HNSCC. We found that NF-kappaB and STAT3 are coactivated together, and with cytokine stimulation or siRNA knock-down, both modulate BAX/BCL-XL. 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.
authors.affiliation: Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892-1419, USA.
authors.forename: Tin Lap
authors.initials: TL
authors.lastname: Lee
authors.forename: Jason
authors.initials: J
authors.lastname: Yeh
authors.forename: Jay
authors.initials: J
authors.lastname: Friedman
authors.forename: Bin
authors.initials: B
authors.lastname: Yan
authors.forename: Xinping
authors.initials: X
authors.lastname: Yang
authors.forename: Ning T
authors.initials: NT
authors.lastname: Yeh
authors.forename: Carter
authors.initials: C
authors.lastname: Van Waes
authors.forename: Zhong
authors.initials: Z
authors.lastname: Chen
mesh_terms: D000912:Antibodies, Neoplasm / Q000378:metabolism; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival; D024202:Electrophoretic Mobility Shift Assay; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D016328:NF-kappa B / Q000378:metabolism*; D010957:Plasmids; D034741:RNA, Small Interfering / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000378:metabolism; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein / Q000378:metabolism*; D051020:bcl-X Protein / Q000378:metabolism*
chemical_list: D000912:Antibodies, Neoplasm; C494826:BAX protein, human; C494811:BCL2L1 protein, human; D014408:Biomarkers, Tumor; D016328:NF-kappa B; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051996:Transcription Factor RelA; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein