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 Blood, 29 October 2009, Vol. 114, No. 18, pp. 3960-3967.
Prepublished online as a Blood First Edition Paper on August 27, 2009; DOI 10.1182/blood-2009-03-209668.

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VASCULAR BIOLOGY

GRP-78 secreted by tumor cells blocks the antiangiogenic activity of bortezomib

Johann Kern1,*, Gerold Untergasser1,*, Christoph Zenzmaier2, Bettina Sarg3, Guenther Gastl1, Eberhard Gunsilius1, and Michael Steurer4

1 Tumor Biology & Angiogenesis Laboratory, Department of Internal Medicine V, Innsbruck Medical University, Innsbruck; 2 Institute for Biomedical Aging Research, Innsbruck; 3 Division of Clinical Chemistry, Biocenter, Innsbruck Medical University, Innsbruck, and 4 Laboratory for Molecular Genetics, Department of Internal Medicine V, Innsbruck Medical University, Innsbruck, Austria

Antiangiogenic effects of the proteasome inhibitor bortezomib were analyzed on tumor xenografts in vivo. Bortezomib strongly inhibited angiogenesis and vascularization in the chicken chorioallantoic membrane. Bortezomib's inhibitory effects on chorioallantoic membrane vascularization were abrogated in the presence of distinct tumor xenografts, thanks to a soluble factor secreted by tumor cells. Through size-exclusion and ion-exchange chromatography as well as mass spectroscopy, we identified GRP-78, a chaperone protein of the unfolded protein response, as being responsible for bortezomib resistance. Indeed, a variety of bortezomib-resistant solid tumor cell lines (PC-3, HRT-18), but not myeloma cell lines (U266, OPM-2), were able to secrete high amounts of GRP-78. Recombinant GRP-78 conferred bortezomib resistance to endothelial cells and OPM-2 myeloma cells. Knockdown of GRP78 gene expression in tumor cells and immunodepletion of GRP-78 protein from tumor cell supernatants restored bortezomib sensitivity. GRP-78 did not bind or complex bortezomib but induced prosurvival signals by phosphorylation of extracellular signal–related kinase and inhibited p53-mediated expression of proapoptotic Bok and Noxa proteins in endothelial cells. From our data, we conclude that distinct solid tumor cells are able to secrete GRP-78 into the tumor microenvironment, thus demonstrating a hitherto unknown mechanism of resistance to bortezomib.


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