A BAP31 intrabody induces gastric cancer cell death by inhibiting p27kip1 proteasome degradation

B-cell receptor-associated protein 31 (BAP31) is a ubiquitously expressed endoplasmic reticulum (ER) membrane protein that has been found to be overexpressed in gastric intestinal-type adenocarcinoma. We first studied the relationship of BAP31 with 84 kinds of tumor-associated antigens and found that BAP31 can specifically interact with and regulate the proteasome degradation of the cyclin kinase inhibitor p27^kip1, which is one of the most frequently dysregulated tumor suppressor proteins in human cancers. Therefore, we screened antibodies against BAP31 from a human VH single-domain antibody library and expressed the antibodies intracellularly. It was found that one of the intrabodies (VH-D1) specifically inhibited p27^kip1 proteasome degradation, possibly by blocking the combination of BAP31 with p27^kip1. VH-D1 displayed therapeutic effects, as it was able to reduce the growth of human gastric cancer (GC) cell xenografts in nude mice. This effect was due to inhibition of the proliferation and subsequent activation of caspase-dependent apoptosis. Thus, BAP31 is a potential target for the suppression of GC via an intrabody-based approach.