Abstract
Receptor-recognized forms of alpha(2)-macroglobulin (alpha(2)M*) bind to cancer cell surface GRP78, which functions as a signaling receptor promoting proliferation and survival. Patients with prostate, ovary, and skin cancer may develop auto-antibodies to the alpha(2)M* binding site which are receptor agonists whose presence indicates a poor prognosis. By contrast, antibodies directed against the COOH-terminal domain of GPR78 (anti-CTD antibody), are antagonists which down regulate pro-proliferative signaling and upregulate p53. Unfolded protein response (UPR) signaling plays an important role in cell survival and proliferation as well as apoptosis. We, therefore, studied the effect of anti-CTD antibody on UPR signaling in 1-LN and DU-145 prostate cancer cells. Treatment of these cells, which express GRP78 on their cell surface, with this antibody significantly downregulated IRE1-alpha, PERK, and ATF6alpha-dependent UPR signaling. By contrast, the pro-apoptotic protein GADD153 was elevated. Anti-CTD antibody treatment also elevated apoptotic components, cleaved PARP-1, and Erdj5. In general, a two to threefold effect was observed for the parameters which were studied. These studies suggest that anti-CTD antibody induces growth inhibitory and pro-apoptotic effects by modulating UPR signaling in human prostate cancer cells.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Antibodies / immunology*
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Antibodies / pharmacology*
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Apoptosis Regulatory Proteins / metabolism
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Bcl-2-Like Protein 11
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Caspases / metabolism
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Cell Line, Tumor
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Down-Regulation / drug effects
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Endoplasmic Reticulum / drug effects
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Endoplasmic Reticulum / pathology
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Endoplasmic Reticulum Chaperone BiP
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Enzyme Activation / drug effects
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Eukaryotic Initiation Factor-2 / metabolism
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Heat-Shock Proteins / chemistry*
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Heat-Shock Proteins / immunology*
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Humans
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Immunoblotting
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Male
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Membrane Proteins / metabolism
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Neoplasm Proteins / metabolism
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Poly(ADP-ribose) Polymerases / metabolism
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Prostatic Neoplasms / enzymology
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Prostatic Neoplasms / metabolism*
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Prostatic Neoplasms / pathology
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt / metabolism
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Transcription Factor CHOP / metabolism
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Unfolded Protein Response / drug effects*
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Up-Regulation / drug effects
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eIF-2 Kinase / metabolism
Substances
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Antibodies
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Apoptosis Regulatory Proteins
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BCL2L11 protein, human
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Bcl-2-Like Protein 11
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DDIT3 protein, human
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Endoplasmic Reticulum Chaperone BiP
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Eukaryotic Initiation Factor-2
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HSPA5 protein, human
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Heat-Shock Proteins
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Membrane Proteins
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Neoplasm Proteins
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Proto-Oncogene Proteins
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Transcription Factor CHOP
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Poly(ADP-ribose) Polymerases
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PERK kinase
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Proto-Oncogene Proteins c-akt
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eIF-2 Kinase
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Caspases