Prostate cancer cell proliferation in vitro is modulated by antibodies against glucose-regulated protein 78 isolated from patient serum

Circulating autoantibodies against the glucose-regulated protein of 78 kDa (GRP78) are present at high levels in prostate cancer patients and are a biomarker of aggressive tumor behavior. We purified the anti-GRP78 IgGs and examined their effect on 1-LN, PC-3, DU145, and LnCap human prostate cancer...

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Published in:Cancer research (Chicago, Ill.) Ill.), 2006-12, Vol.66 (23), p.11424-11431
Main Authors: GONZALEZ-GRONOW, Mario, CUCHACOVICH, Miguel, LLANOS, Carolina, URZUA, Cristian, GAWDI, Govind, PIZZO, Salvatore V
Format: Article
Language:English
Subjects:
alpha-Macroglobulins - immunology
alpha-Macroglobulins - metabolism
Amino Acid Sequence
Animals
Antibody Affinity - immunology
Antigen-Antibody Reactions - immunology
Antineoplastic agents
Apoptosis - drug effects
Autoantibodies - blood
Autoantibodies - pharmacology
Binding Sites, Antibody - genetics
Binding Sites, Antibody - immunology
Biological and medical sciences
Blotting, Western
Cell Line, Tumor
Cell Membrane - immunology
Cell Proliferation - drug effects
Dose-Response Relationship, Drug
Epitopes - genetics
Epitopes - immunology
Gynecology. Andrology. Obstetrics
Heat-Shock Proteins - immunology
Humans
Immunoglobulin G - blood
Immunoglobulin G - pharmacology
Male
Male genital diseases
Medical sciences
Molecular Chaperones - immunology
Molecular Sequence Data
Nephrology. Urinary tract diseases
Pharmacology. Drug treatments
Prostate-Specific Antigen - blood
Prostatic Neoplasms - blood
Prostatic Neoplasms - immunology
Prostatic Neoplasms - pathology
Tumor Necrosis Factor-alpha - pharmacology
Tumors
Tumors of the urinary system
Urinary tract. Prostate gland
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Summary:Circulating autoantibodies against the glucose-regulated protein of 78 kDa (GRP78) are present at high levels in prostate cancer patients and are a biomarker of aggressive tumor behavior. We purified the anti-GRP78 IgGs and examined their effect on 1-LN, PC-3, DU145, and LnCap human prostate cancer cells. We also evaluated its effects on the breast cancer MDA-MB231 and melanoma DM413 cell lines. The anti-GRP78 antibody binds only to cells expressing GRP78 on the surface, to a site also recognized by its physiologic agonist, activated alpha(2)-macroglobulin (alpha(2)M*). This antibody is completely specific for a peptide, including the primary amino acid sequence CNVKSDKSC, which contains a tertiary structural motif mimicking an epitope in GRP78. Tertiary structural analysis suggested the linear GRP78 primary amino acid sequence LIGRTWNDPSVQQDIKFL (Leu(98)-Leu(115)) as the putative binding site, containing the tertiary structual arrangement described above, which was confirmed experimentally. The anti-GRP78 antibodies from prostate cancer patients recognize almost exclusively this epitope. We produced animal antibodies against both these peptides, and they are able to mimic the effects of the human antibody. Our experiments also suggest this epitope as highly immunogenic, thereby explaining the specificity of the immune response against this epitope in GRP78, observed in humans. Using 1-LN cells as a model, we show that anti-GRP78 IgG purified from the sera of these patients mimics the proproliferative effects induced by alpha(2)M* via the common receptor, GRP78. Furthermore, increasing concentrations of human anti-GRP78 IgG show a dose-dependent protective effect on apoptosis induced by tumor necrosis factor alpha.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-06-1721