Title | NF-kappaB is essential for the progression of KSHV- and EBV-infected lymphomas in vivo. |
Publication Type | Journal Article |
Year of Publication | 2006 |
Authors | Keller SA, Hernandez-Hopkins D, Vider J, Ponomarev V, Hyjek E, Schattner EJ, Cesarman E |
Journal | Blood |
Volume | 107 |
Issue | 8 |
Pagination | 3295-302 |
Date Published | 2006 Apr 15 |
ISSN | 0006-4971 |
Keywords | Animals, Apoptosis, Cell Line, Tumor, Gene Expression Regulation, Leukemic, Gene Expression Regulation, Viral, Herpesvirus 4, Human, Herpesvirus 8, Human, Humans, Lymphoma, Mice, Mice, Inbred NOD, Mice, SCID, Mitochondria, Neoplasm Transplantation, Neoplasms, Experimental, NF-kappa B, Nitriles, Sulfones, Virus Replication |
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. |
DOI | 10.1182/blood-2005-07-2730 |
Alternate Journal | Blood |
PubMed ID | 16380446 |
PubMed Central ID | PMC1432097 |
Grant List | R01 CA068939 / CA / NCI NIH HHS / United States R01-CA68939 / CA / NCI NIH HHS / United States |
Related Faculty:
Ethel Cesarman, M.D., Ph.D.