Activation of the nuclear factor κB pathway by astrocyte elevated gene-1 : Implications for tumor progression and metastasis

• Published in: Cancer research (Chicago, Ill.) Vol. 66; no. 3; pp. 1509 - 1516
• Main Authors: EMDAD, Luni, SARKAR, Devanand, SU, Zao-Zhong, RANDOLPH, Aaron, BOUKERCHE, Habib, VALERIC, Kristoffer, FISHER, Paul B
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.02.2006
• Subjects: Adenovirus; Biological and medical sciences; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Fundamental and applied biological sciences. Psychology; Human immunodeficiency virus; Molecular and cellular biology; Gene; Neuroglia; Tumor progression; Genetics; Astrocyte; Transcription factor NFκB; Metastasis; Malignant tumor
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-05-3029

Abstract Astrocyte elevated gene-1 (AEG-1) was initially identified as an HIV-1- and tumor necrosis factor α (TNF-α)–inducible transcript in primary human fetal astrocytes by a rapid subtraction hybridization approach. Interestingly, AEG-1 expression is elevated in subsets of breast cancer, glioblastoma multiforme and melanoma cells and AEG-1 cooperates with Ha-ras to promote transformation of immortalized melanocytes. Activation of the transcription factor nuclear factor κB (NF-κB), a TNF-α downstream signaling component, is associated with several human illnesses, including cancer, and NF-κB controls the expression of multiple genes involved in tumor progression and metastasis. We now document that AEG-1 is a significant positive regulator of NF-κB. Enhanced expression of AEG-1 via a replication-incompetent adenovirus (Ad.AEG-1) in HeLa cells markedly increased binding of the transcriptional activator p50/p65 complex of NF-κB. The NF-κB activation induced by AEG-1 corresponded with degradation of IκBα and nuclear translocation of p65 that resulted in the induction of NF-κB downstream genes. Infection with an adenovirus expressing the mt32IκBα superrepressor (Ad.IκBα-mt32), which prevents p65 nuclear translocation, inhibited AEG-1-induced enhanced agar cloning efficiency and increased matrigel invasion of HeLa cells. We also document that TNF-α treatment resulted in nuclear translocation of both AEG-1 and p65 wherein these two proteins physically interacted, suggesting a potential mechanism by which AEG-1 could activate NF-κB. Our findings suggest that activation of NF-κB by AEG-1 could represent a key molecular mechanism by which AEG-1 promotes anchorage-independent growth and invasion, two central features of the neoplastic phenotype. (Cancer Res 2006; 66(3): 1509-16)