Chaperone
proteins and
heat shock proteins (HSP) are essential components of cellular protein folding systems under normal conditions; their expression and activities are upregulated during stress. Chronically stressed
tumors frequently exhibit high chaperone
protein levels, exploiting their anti-apoptotic mechanisms and general
proteome homeostasis amidst a background of genetic instability. Co-chaperones interact with chaperones as malleable regulatory components of protein folding activity and may represent a conduit for modification of chaperone activity to the detriment of the
tumor. We have initially characterized one such co-chaperone,
heat shock protein 70-binding
protein (HspBP) 1 from human
brain tumors, their xenografts grown in immune-compromised mice, and in syngeneic murine models in immune-competent mice. Immunohistochemical analyses show HspBP1 overexpression (with unusual subcellular localizations) in patient
brain tumors relative to normal brain tissue. This holds true for the xenograft and syngeneic murine
tumor models. In biochemical affinity chromatography assays, HspBP1 interacts with members of the HSP70 family from
brain tumor lysates and from surface-derived samples, including HSP70,
glucose regulated
protein (GRP)75,
GRP78, and HSP110. From normal brain lysates, only heat shock cognate (HSC)70,
GRP75, and HSP110 bind to HspBP1. FACS analyses indicate that HspBP1 binds to
brain tumor cell surfaces, possibly via HSP70 family members, and internalizes into cells. This has implications for HspBP1 biology as well as its utility as a
tumor-targeting agent. Our results suggest that HspBP1 may play a role in
tumor (dys)regulation of chaperone
proteins, and that HspBP1 may have extracellular roles with therapeutic implications.