Activation of NF-kappaB signaling by inhibitor of NF-kappaB kinase beta increases aggressiveness of ovarian cancer.
The NF-kappaB family of transcription factors has been implicated in the propagation of ovarian cancer, but the significance of constitutive NF-kappaB signaling in ovarian cancer is unknown. We hypothesized that constitutive NF-kappaB signaling defines a subset of ovarian cancer susceptible to therapeutic targeting of this pathway. We investigated the biological relevance of NF-kappaB in ovarian cancer using a small-molecule inhibitor of inhibitor of NF-kappaB kinase beta (IKKbeta) and confirmed with RNA interference toward IKKbeta. We developed a gene expression signature of IKKbeta signaling in ovarian cancer using both pharmacologic and genetic manipulation of IKKbeta. The expression of IKKbeta protein itself and the nine-gene ovarian cancer-specific IKKbeta signature were related to poor outcome in independently collected sets of primary ovarian cancers (P = 0.02). IKKbeta signaling in ovarian cancer regulated the transcription of genes involved in a wide range of cellular effects known to increase the aggressive nature of the cells. We functionally validated the effect of IKKbeta signaling on proliferation, invasion, and adhesion. Downregulating IKKbeta activity, either by a small-molecule kinase inhibitor or by short hairpin RNA depletion of IKKbeta, blocked all of these cellular functions, reflecting the negative regulation of the target genes identified. The diversity of functions controlled by IKKbeta in ovarian cancer suggests that therapeutic blockade of this pathway could be efficacious if specific IKKbeta inhibitor therapy is focused to patients whose tumors express a molecular profile suggestive of dependence on IKKbeta activity.
Hernandez
Lídia
L
Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892-1906, USA.
Hsu
Sarah C
SC
Davidson
Ben
B
Birrer
Michael J
MJ
Kohn
Elise C
EC
Annunziata
Christina M
CM
D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D002243:Carbolines / Q000494:pharmacology; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D008875:Middle Aged; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D046888:Tissue Array Analysis; D014407:Tumor Cells, Cultured
D014408:Biomarkers, Tumor; D002243:Carbolines; C514957:N-(6-chloro-7-methoxy-9H-beta-carbolin-8-yl)-2-methylnicotinamide; D016328:NF-kappa B; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D009536:Niacinamide; D051550:I-kappa B Kinase; C496560:IKBKB protein, human