Differences in Glycosylation Patterns of Heat Shock Protein, gp96: Implications for Prostate Cancer Prevention

Abstract

Heat shock protein gp96 induces a tumor-specific protective immunity in a variety of experimental tumor models. Because the primary sequences of the glycoprotein, gp96 are identical between tumor and normal tissues, the peptides associated with gp96 and/or the posttranslational modifications of gp96, determine its immunogenicity. Gp96-associated peptides constitute the antigenic repertoire of the source tissue; thus, purified gp96-peptide complexes have clinical significance as autologous cancer vaccines. However, the role of altered glycosylation and its contribution in the biological as well as immunologic activity of gp96 still remains uncharacterized. We examined the cancer-specific glycosylation patterns of gp96. To this end, monosaccharide compositions of gp96 were compared between normal rat prostate and two cancerous rat prostate tissues, nonmetastatic/androgen-dependent Dunning G and metastatic/androgen-independent MAT-LyLu, as well as two human nonmetastatic prostate cancer cell lines, androgen-dependent LnCaP and androgen-independent DU145. Marked differences were observed between the gp96 monosaccharide compositions of the normal and cancerous tissues. Furthermore, gp96 molecules from more aggressive cellular transformations were found to carry decreasing quantities of several monosaccharides as well as sum total content of neutral and amino sugars. We believe that the unique glycosylation patterns contribute to cellular phenotype and that the posttranslational modifications of gp96 may affect its functional attributes. (Cancer Res 2005; 65(14): 6466-75)

Integrated Proteomic and Glycoproteomic Analyses of Prostate Cancer Cells Reveal Glycoprotein Alteration in Protein Abundance and Glycosylation*

“…HSP90B1 purified from tumors initiates a tumor-specific cytotoxic T-cell lymphocyte response (39,40). The amino acid sequences of HSP90B1 from tumor and normal tissues are identical; (41) however, fucosylation differences between cancerous and normal tissue have been observed (42), suggesting a role of glycosylation in the cancerspecific immune system response and also emphasizing the importance of studying glycosylation.…”

A new tumor-specific variant of GRP78 as target for antibody-based therapy

“…26,53 Recently, a variant of GRP94, modified in its carbohydrate structure, was detected in more aggressive cancer prostate tissues but not normal tissues. 54 The modifications are in all cases found in the carbohydrate structure of the molecule and in part, are coexpressed with their wild types on the tumor cell surface. This is not surprising because malignant cells often modify their carbo-pattern by post-transcriptional activity in adaption to their elevated and new needs of growth factors, protection factors, adhesion molecules etc.…”

gp96 Is a Human Colonocyte Plasma Membrane Binding Protein for Clostridium difficile Toxin A

“…gp96 is composed of 803 amino acids with five potential N-linked glycosylation sites (28), but the glycan moieties of this molecule have not been studied in detail. gp96 was found to have different glycosylation patterns between various tumors, and the presence or absence of specific glycosyl motifs was associated with variations in cancer phenotype (40). Detailed structural characterization of gp96 glycan motifs in colonic epithelial cells may be required to further characterize gp96 interaction with TxA.…”