The role of NF-κB-1 and NF-κB-2-mediated resistance to apoptosis in lymphomas

doi:10.1073/pnas.0507809103

The role of NF-κB-1 and NF-κB-2-mediated resistance to apoptosis in lymphomas

*Division of Molecular Oncology, Departments of
^†Medicine,
^§Cell Biology, and
^¶Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110; and
^‡Division of Hematology and Oncology, Department of Medicine, Emory University, Atlanta, GA 30322

Edited by Michael Karin, University of California at San Diego School of Medicine, La Jolla, CA, and approved May 2, 2006 (received for review September 7, 2005)

Abstract

The NF-κB pathways have been implicated in tumorigenesis in several lymphoid malignancies, including non-Hodgkin's and Hodgkin's lymphomas. However, the antiapoptotic functions and the mechanism responsible for signaling through each NF-κB pathway remain to be elucidated. In the current study, lymphoma cell lines with constitutively active NF-κB were found to be resistant to inducers of the extrinsic and intrinsic apoptosis pathways. Resistance to cell death resulted from blocks early and late in the apoptosis cascade. Several NF-κB target genes were overexpressed in these cell lines, including Bcl-xL, Fas-associated death domain-like IL-1β-converting enzyme inhibitor protein, cellular inhibitor of apoptosis, and X inhibitor of apoptosis. Inhibition of the canonical or noncanonical NF-κB pathways with small interfering RNAs or adenovirus expressing a stable form of inhibitor of NF-κB (IκB) enhanced sensitivity to apoptosis inducers and resulted in lower levels of Bcl-xL or Fas-associated death domain-like IL-1β-converting enzyme inhibitor protein, cellular inhibitor of apoptosis, and X inhibitor of apoptosis. These findings demonstrate an important role of both NF-κB pathways in mediating resistance to apoptosis and distinctive antiapoptotic downstream target gene profiles responsible for this effect.

Footnotes

^‖To whom correspondence should be addressed. E-mail: lratner{at}im.wustl.edu
Author contributions: L.R. designed research; L.B.-M. and L.R. performed research; C.M.L. contributed new reagents/analytic tools; L.B.-M. analyzed data; and L.B.-M. and L.R. wrote the paper.
Conflict of interest statement: No conflicts declared.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

Abbreviations:

EBV,

Epstein–Barr virus;

HTLV,

human T cell leukemia virus;

NF-κB-ca,

constitutively active NF-κB;

FLIP,

Fas-associated death domain-like IL-1β-converting enzyme inhibitory protein;

CIAP,

cellular inhibitor of apoptosis;

XIAP,

X inhibitor of apoptosis;

TRAIL,

TNF-related apoptosis-inducing ligand;

PI,

propidium iodide;

IKK,

IκB kinase;

siRNA,

short interfering RNA