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

Publication ,  Journal Article
Al-Hashimi, AA; Lebeau, P; Majeed, F; Polena, E; Lhotak, Š; Collins, CAF; Pinthus, JH; Gonzalez-Gronow, M; Hoogenes, J; Pizzo, SV; Crowther, M ...
Published in: J Biol Chem
December 22, 2017

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.

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Published In

J Biol Chem

DOI

EISSN

1083-351X

Publication Date

December 22, 2017

Volume

292

Issue

51

Start / End Page

21180 / 21192

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Unfolded Protein Response
  • Tumor Burden
  • Thromboplastin
  • Surface Properties
  • Recombinant Proteins
  • Random Allocation
  • Prostatic Neoplasms
  • Prostate-Specific Antigen
  • Prostate
 

Citation

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Al-Hashimi, A. A., Lebeau, P., Majeed, F., Polena, E., Lhotak, Š., Collins, C. A. F., … Austin, R. C. (2017). Autoantibodies against the cell surface-associated chaperone GRP78 stimulate tumor growth via tissue factor. J Biol Chem, 292(51), 21180–21192. https://doi.org/10.1074/jbc.M117.799908
Al-Hashimi, Ali A., Paul Lebeau, Fadwa Majeed, Enio Polena, Šárka Lhotak, Celeste A. F. Collins, Jehonathan H. Pinthus, et al. “Autoantibodies against the cell surface-associated chaperone GRP78 stimulate tumor growth via tissue factor.J Biol Chem 292, no. 51 (December 22, 2017): 21180–92. https://doi.org/10.1074/jbc.M117.799908.
Al-Hashimi AA, Lebeau P, Majeed F, Polena E, Lhotak Š, Collins CAF, et al. Autoantibodies against the cell surface-associated chaperone GRP78 stimulate tumor growth via tissue factor. J Biol Chem. 2017 Dec 22;292(51):21180–92.
Al-Hashimi, Ali A., et al. “Autoantibodies against the cell surface-associated chaperone GRP78 stimulate tumor growth via tissue factor.J Biol Chem, vol. 292, no. 51, Dec. 2017, pp. 21180–92. Pubmed, doi:10.1074/jbc.M117.799908.
Al-Hashimi AA, Lebeau P, Majeed F, Polena E, Lhotak Š, Collins CAF, Pinthus JH, Gonzalez-Gronow M, Hoogenes J, Pizzo SV, Crowther M, Kapoor A, Rak J, Gyulay G, D’Angelo S, Marchiò S, Pasqualini R, Arap W, Shayegan B, Austin RC. Autoantibodies against the cell surface-associated chaperone GRP78 stimulate tumor growth via tissue factor. J Biol Chem. 2017 Dec 22;292(51):21180–21192.

Published In

J Biol Chem

DOI

EISSN

1083-351X

Publication Date

December 22, 2017

Volume

292

Issue

51

Start / End Page

21180 / 21192

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Unfolded Protein Response
  • Tumor Burden
  • Thromboplastin
  • Surface Properties
  • Recombinant Proteins
  • Random Allocation
  • Prostatic Neoplasms
  • Prostate-Specific Antigen
  • Prostate