Protein kinase CK2 promotes aberrant activation of nuclear factor-kappaB, transformed phenotype, and survival of breast cancer cells.
The Her-2/neu oncogene, the second member of the epidermal growth factor (EGF) receptor family, encodes a transmembrane tyrosine kinase receptor. Overexpression of Her-2/neu in approximately 30% of breast cancers is associated with poor overall survival. Recently, we have found that Her-2/neu activates nuclear factor (NF)-kappaB via a phosphatidylinositol 3 kinase (PI3-K)-Akt kinase signaling pathway in mouse mammary tumor virus (MMTV)-Her-2/neu NF639 mouse breast cancer cells. Surprisingly, the IkappaB kinase (IKK) kinase complex, implicated in proteasome-mediated degradation of IkappaB-alpha and activation of NF-kappaB via the canonical pathway, was not activated in these cells. Degradation of IkappaB-alpha was mediated via calpain, which in B cells is facilitated by phosphorylation of IkappaB-alpha by the protein kinase CK2. Here, we report that the inhibition of CK2 blocks Her-2/neu-mediated activation of NF-kappaB. NF639 breast cancer cells, stably expressing CK2alpha or CK2alpha' kinase-inactive mutants, displayed decreased NF-kappaB binding and reduced ability to grow in soft agar, as well as increased sensitivity to tumor necrosis factor (TNF)-alpha killing. Similarly, CK2 kinase-inactive subunits inhibited NF-kappaB activity in Hs578T human breast cancer cells, which also display elevated CK2 activity. In NIH 3T3 fibroblasts, which express low basal NF-kappaB and CK2 activities, overexpression of CK2 by retroviral gene delivery led to increased IkappaB-alpha turnover and the induction of classical NF-kappaB (p50/RelA). Thus, CK2 plays an important role in Her-2/neu signaling, promoting IkappaB-alpha degradation and, thereby, NF-kappaB activation. Furthermore, because ectopic CK2 activity appears sufficient to induce NF-kappaB, the elevated CK2 activity observed in many primary human breast cancers likely plays a role in aberrant activation of NF-kappaB and, therefore, represents a potential therapeutic target.
Romieu-Mourez
Raphaëlle
R
Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118-2394, USA.
Landesman-Bollag
Esther
E
Seldin
David C
DC
Sonenshein
Gail E
GE
D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D047390:Casein Kinase II; D002470:Cell Survival / Q000502:physiology; D002471:Cell Transformation, Neoplastic; D005784:Gene Amplification; D018734:Genes, erbB-2; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007668:Kidney / Q000166:cytology / Q000201:enzymology; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured
D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D000072000:NF-KappaB Inhibitor alpha; D047390:Casein Kinase II; D017346:Protein Serine-Threonine Kinases