NF-kappaB is essential for the progression of KSHV- and EBV-infected lymphomas in vivo. Academic Article uri icon

Overview

abstract

  • 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.

publication date

  • December 27, 2005

Research

keywords

  • Gene Expression Regulation, Leukemic
  • Gene Expression Regulation, Viral
  • Herpesvirus 4, Human
  • Herpesvirus 8, Human
  • Lymphoma
  • NF-kappa B
  • Nitriles
  • Sulfones

Identity

PubMed Central ID

  • PMC1432097

Scopus Document Identifier

  • 33645748053

Digital Object Identifier (DOI)

  • 10.1182/blood-2005-07-2730

PubMed ID

  • 16380446

Additional Document Info

volume

  • 107

issue

  • 8