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Autoantibodies against the cell surface-associated chaperone GRP78 stimulate tumor growth via tissue factor.

Abstract
Tumor cells display on their surface several molecular chaperones that normally reside in the endoplasmic reticulum. Because this display is unique to cancer cells, these chaperones are attractive targets for drug development. Previous epitope-mapping of autoantibodies (AutoAbs) from prostate cancer patients identified the 78-kDa glucose-regulated protein (GRP78) as one such target. Although we previously showed that anti-GRP78 AutoAbs increase tissue factor (TF) procoagulant activity on the surface of tumor cells, the direct effect of TF activation on tumor growth was not examined. In this study, we explore the interplay between the AutoAbs against cell surface-associated GRP78, TF expression/activity, and prostate cancer progression. First, we show that tumor GRP78 expression correlates with disease stage and that anti-GRP78 AutoAb levels parallel prostate-specific antigen concentrations in patient-derived serum samples. Second, we demonstrate that these anti-GRP78 AutoAbs target cell-surface GRP78, activating the unfolded protein response and inducing tumor cell proliferation through a TF-dependent mechanism, a specific effect reversed by neutralization or immunodepletion of the AutoAb pool. Finally, these AutoAbs enhance tumor growth in mice bearing human prostate cancer xenografts, and heparin derivatives specifically abrogate this effect by blocking AutoAb binding to cell-surface GRP78 and decreasing TF expression/activity. Together, these results establish a molecular mechanism in which AutoAbs against cell-surface GRP78 drive TF-mediated tumor progression in an experimental model of prostate cancer. Heparin derivatives counteract this mechanism and, as such, represent potentially appealing compounds to be evaluated in well-designed translational clinical trials.
AuthorsAli A Al-Hashimi, Paul Lebeau, Fadwa Majeed, Enio Polena, Šárka Lhotak, Celeste A F Collins, Jehonathan H Pinthus, Mario Gonzalez-Gronow, Jen Hoogenes, Salvatore V Pizzo, Mark Crowther, Anil Kapoor, Janusz Rak, Gabriel Gyulay, Sara D'Angelo, Serena Marchiò, Renata Pasqualini, Wadih Arap, Bobby Shayegan, Richard C Austin
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 292 Issue 51 Pg. 21180-21192 (12 22 2017) ISSN: 1083-351X [Electronic] United States
PMID29066620 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
Chemical References
  • Antineoplastic Agents
  • Autoantibodies
  • Endoplasmic Reticulum Chaperone BiP
  • HSPA5 protein, human
  • Heat-Shock Proteins
  • Hspa5 protein, mouse
  • Neoplasm Proteins
  • Recombinant Proteins
  • Thromboplastin
  • Prostate-Specific Antigen
Topics
  • Animals
  • Antineoplastic Agents (chemistry, metabolism, therapeutic use)
  • Autoantibodies (analysis, metabolism, toxicity)
  • Cell Line, Tumor
  • Cell Membrane (drug effects, immunology, metabolism, pathology)
  • Cell Proliferation (drug effects)
  • Endoplasmic Reticulum Chaperone BiP
  • Heat-Shock Proteins (antagonists & inhibitors, genetics, metabolism, therapeutic use)
  • Humans
  • Male
  • Mice, Inbred NOD
  • Mice, SCID
  • Neoplasm Grading
  • Neoplasm Proteins (antagonists & inhibitors, genetics, metabolism, therapeutic use)
  • Neoplasm Staging
  • Prostate (drug effects, immunology, metabolism, pathology)
  • Prostate-Specific Antigen (blood)
  • Prostatic Neoplasms (drug therapy, immunology, metabolism, pathology)
  • Random Allocation
  • Recombinant Proteins (chemistry, metabolism, therapeutic use)
  • Surface Properties
  • Thromboplastin (agonists, analysis, metabolism)
  • Tumor Burden (drug effects)
  • Unfolded Protein Response (drug effects)
  • Xenograft Model Antitumor Assays

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