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

Ali 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

Research output: Contribution to journalArticle

3 Citations (Scopus)

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 epitopemapping 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.

Original languageEnglish
Pages (from-to)21180-21192
Number of pages13
JournalJournal of Biological Chemistry
Volume292
Issue number51
DOIs
Publication statusPublished - Jan 1 2017

Fingerprint

Thromboplastin
Autoantibodies
Tumors
Growth
Neoplasms
Prostatic Neoplasms
Cells
Heparin
Bearings (structural)
Derivatives
Molecular Chaperones
Unfolded Protein Response
Cell proliferation
Prostate-Specific Antigen
Heterografts
Endoplasmic Reticulum
Chemical activation
Display devices
Theoretical Models
Cell Proliferation

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

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. Journal of Biological Chemistry, 292(51), 21180-21192. https://doi.org/10.1074/jbc.M117.799908

Autoantibodies against the cell surface-Associated chaperone GRP78 stimulate tumor growth via tissue factor. / Al-Hashimi, Ali A.; Lebeau, Paul; Majeed, Fadwa; Polena, Enio; Lhotak, Šárka; Collins, Celeste A.F.; Pinthus, Jehonathan H.; Gonzalez-Gronow, Mario; Hoogenes, Jen; Pizzo, Salvatore V.; Crowther, Mark; Kapoor, Anil; Rak, Janusz; Gyulay, Gabriel; D'Angelo, Sara; Marchiò, Serena; Pasqualini, Renata; Arap, Wadih; Shayegan, Bobby; Austin, Richard C.

In: Journal of Biological Chemistry, Vol. 292, No. 51, 01.01.2017, p. 21180-21192.

Research output: Contribution to journalArticle

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 2017, 'Autoantibodies against the cell surface-Associated chaperone GRP78 stimulate tumor growth via tissue factor', Journal of Biological Chemistry, vol. 292, no. 51, pp. 21180-21192. https://doi.org/10.1074/jbc.M117.799908
Al-Hashimi, Ali A. ; Lebeau, Paul ; Majeed, Fadwa ; Polena, Enio ; Lhotak, Šárka ; Collins, Celeste A.F. ; Pinthus, Jehonathan H. ; Gonzalez-Gronow, Mario ; Hoogenes, Jen ; Pizzo, Salvatore V. ; Crowther, Mark ; Kapoor, Anil ; Rak, Janusz ; Gyulay, Gabriel ; D'Angelo, Sara ; Marchiò, Serena ; Pasqualini, Renata ; Arap, Wadih ; Shayegan, Bobby ; Austin, Richard C. / Autoantibodies against the cell surface-Associated chaperone GRP78 stimulate tumor growth via tissue factor. In: Journal of Biological Chemistry. 2017 ; Vol. 292, No. 51. pp. 21180-21192.
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AU - Majeed, Fadwa

AU - Polena, Enio

AU - Lhotak, Šárka

AU - Collins, Celeste A.F.

AU - Pinthus, Jehonathan H.

AU - Gonzalez-Gronow, Mario

AU - Hoogenes, Jen

AU - Pizzo, Salvatore V.

AU - Crowther, Mark

AU - Kapoor, Anil

AU - Rak, Janusz

AU - Gyulay, Gabriel

AU - D'Angelo, Sara

AU - Marchiò, Serena

AU - Pasqualini, Renata

AU - Arap, Wadih

AU - Shayegan, Bobby

AU - Austin, Richard C.

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N2 - 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 epitopemapping 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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