title: Notch is an essential upstream regulator of NF-κB and is relevant for survival of Hodgkin and Reed-Sternberg cells.
abstract: A major pathogenetic mechanism in classical Hodgkin lymphoma (cHL) is constitutive activation of canonical nuclear factor-κB (NF-κB) p50/p65 signaling, controlling lymphoma cell proliferation and survival. Recently, we demonstrated that aberrant Notch1 activity is a negative regulator of the B cell program in B cell-derived Hodgkin and Reed-Sternberg (HRS) cells. Despite abundant evidence for a complex context-dependent cross talk between Notch and NF-κB signaling in hematopoietic cells, it is unknown whether these pathways interact in HRS cells. Here, we show that Notch-signaling inhibition in HRS cells by the γ-secretase inhibitor (GSI) XII results in decreased alternative p52/RelB NF-κB signaling, interfering with processing of the NF-κB2 gene product p100 into its active form p52. As a result, expression of Notch and NF-κB target genes is reduced, and survival of HRS cells is impaired. Stimulation of alternative NF-κB signaling in the Hodgkin cell line L540cy by activation of the CD30 receptor rescued GSI-mediated loss of cell viability and apoptosis induction. Our data reveal that Notch is an essential upstream regulator of alternative NF-κB signaling and indicate cross talk between both the pathways in HRS cells. Therefore, we suggest that targeting the Notch pathway is a promising therapeutic option in cHL.
authors.affiliation: Department of Hematology and Oncology, Charité, Campus Virchow-Klinikum, University Medicine Berlin, Berlin, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Schwarzer
authors.forename: B
authors.initials: B
authors.lastname: Dörken
authors.forename: F
authors.initials: F
authors.lastname: Jundt
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival; D006689:Hodgkin Disease / Q000188:drug therapy / Q000473:pathology*; D006801:Humans; D017730:Ki-1 Antigen / Q000502:physiology; D051379:Mice; D016328:NF-kappa B / Q000502:physiology*; D041681:NIH 3T3 Cells; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000502:physiology*; D016539:Reed-Sternberg Cells / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D017730:Ki-1 Antigen; D016328:NF-kappa B; D051880:Receptors, Notch; D053829:Amyloid Precursor Protein Secretases