Inhibition of NF-kappaB1 and NF-kappaB2 activation in prostate cancer cells treated with antibody against the carboxyl terminal domain of GRP78: effect of p53 upregulation.

Abstract

Ligation of cancer cell surface GRP78 by activated alpha2-macroglobulin (alpha2M*) triggers pro-proliferative and anti-apoptotic signaling pathways. Cancer patients who develop autoantibodies to the alpha2M* binding site in GRP78 have a poor prognosis since these antibodies are receptor agonists. The NF-kappaB family of transcription factors induces expression of genes affecting cell growth and differentiation. NF-kappaB1 plays a major regulatory role in controlling innate immunity and inflammation, whereas NF-kappaB2 plays a greater role in cancer cell proliferation. Here we report that treatment of prostate cancer cells with antibody directed against the carboxyl terminal domain of GRP78 inhibits alpha2M*-induced activation of NF-kappaB2 by approximately 50% while exerting a lesser effect of approximately 20% on NF-kappaB1 activation. Treatment of these cells nearly abolished alpha2M*-induced activation of IKKalpha involved in the activation of NF-kappaB2. This antibody also suppressed alpha2M*-induced phosphorylation of IKKalpha, IKKalpha/beta, IkappaBalpha, and IkappaBbeta as well as levels of NIK. Antibody treatment of cancer cells elevated pro-apoptotic p21WAF and p27kip while reducing cyclin D1 levels. These studies demonstrate that antibody directed against the carboxyl terminal domain of GRP78 inhibits the pro-proliferative NF-kappaB signaling cascade in cancer cells.

• Authors: U K Misra, S Kaczowka, S V Pizzo
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 392 Issue 4 Pg. 538-42 (Feb 19 2010) ISSN: 1090-2104 [Electronic] United States
• PMID: 20097177 (Publication Type: Journal Article)
• Copyright: Copyright (c) 2010 Elsevier Inc. All rights reserved.

Chemical References

• Antibodies, Neoplasm
• Autoantibodies
• CDKN1A protein, human
• Cyclin-Dependent Kinase Inhibitor p21
• Endoplasmic Reticulum Chaperone BiP
• HSPA5 protein, human
• Heat-Shock Proteins
• NF-kappa B p50 Subunit
• NF-kappa B p52 Subunit
• Tumor Suppressor Protein p53
• alpha-Macroglobulins
• Cyclin D1
• Cyclin-Dependent Kinase Inhibitor p27

Topics

• Antibodies, Neoplasm (pharmacology)
• Autoantibodies (pharmacology)
• Cell Line, Tumor
• Cell Proliferation
• Cyclin D1 (metabolism)
• Cyclin-Dependent Kinase Inhibitor p21 (metabolism)
• Cyclin-Dependent Kinase Inhibitor p27 (metabolism)
• Endoplasmic Reticulum Chaperone BiP
• Heat-Shock Proteins (immunology, metabolism)
• Humans
• Male
• NF-kappa B p50 Subunit (agonists, antagonists & inhibitors)
• NF-kappa B p52 Subunit (agonists, antagonists & inhibitors)
• Prostatic Neoplasms (metabolism, pathology)
• Protein Structure, Tertiary
• Tumor Suppressor Protein p53 (metabolism)
• alpha-Macroglobulins (immunology, metabolism)