NF-kappaB is essential for the progression of KSHV- and EBV-infected lymphomas in vivo.
Activated NF-kappaB is a critical mechanism by which lymphoma cells infected by Epstein-Barr virus (EBV/HHV-4) and Kaposi sarcoma herpesvirus (KSHV/HHV-8) are protected from apoptotic stress. Selective pharmacologic inhibition of constitutive NF-kappaB activity induces apoptosis in KSHV- and EBV-infected lymphoma cells. In both tumor types, pharmacologic inhibition of NF-kappaB in vitro induced identical mitochondrially mediated apoptosis cascades. Assessment of gene regulation by microarray analysis revealed that the inhibition of NF-kappaB in tumor cells results in the down-regulation of a distinct group of prosurvival genes, including cIAP-1, cIAP-2, cFLIP, and IL-6. Using EBV- and KSHV-associated lymphomas in a murine system, we demonstrated that Bay 11-7082, a selective pharmacologic inhibitor of NF-kappaB, prevents or delays tumor growth and prolongs disease-free survival. Inhibition of NF-kappaB activity and tumor growth responses were further documented using a traceable reporter KSHV-positive cell line and in vivo imaging. These findings indicate that specific NF-kappaB-regulated survival factors work cooperatively to protect KSHV- and EBV-infected lymphoma cells from apoptosis such that they promote the establishment and progression of KSHV- and EBV-associated lymphomas in mice. They also support the use of selective NF-kappaB inhibitors in the treatment of herpesvirus-associated lymphomas.
Keller
Shannon A
SA
Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, 1300 York Ave, New York, NY 10021, USA.
Hernandez-Hopkins
Denise
D
Vider
Jelena
J
Ponomarev
Vladimir
V
Hyjek
Elizabeth
E
Schattner
Elaine J
EJ
Cesarman
Ethel
E
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects* / Q000235:genetics; D015967:Gene Expression Regulation, Viral / Q000187:drug effects* / Q000235:genetics; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000378:metabolism*; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009368:Neoplasm Transplantation / Q000379:methods; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000821:virology; D009570:Nitriles / Q000008:administration & dosage* / Q000627:therapeutic use; D013450:Sulfones / Q000008:administration & dosage* / Q000627:therapeutic use; D014779:Virus Replication / Q000187:drug effects / Q000235:genetics
C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D016328:NF-kappa B; D009570:Nitriles; D013450:Sulfones