A BAP31 intrabody induces gastric cancer cell death by inhibiting p27^kip1 proteasome degradation

Abstract

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 p27kip1, 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 p27kip1 proteasome degradation, possibly by blocking the combination of BAP31 with p27kip1. 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.

Structure and Function of Mitochondria‐Associated Endoplasmic Reticulum Membranes (MAMs) and Their Role in Cardiovascular Diseases

“…Also, the formation of the Fis1-BAP31-tethering complex can be induced by exogenous inducers of apoptosis [43]. Consistent with the previous data, cell apoptosis-related to Fis1 overexpression is associated with the excessive ERmitochondria Ca 2+ transfer [130].…”

BAP31 Promotes Tumor Cell Proliferation by Stabilizing SERPINE2 in Hepatocellular Carcinoma

“…The abnormal high expression of BAP31 was initially detected in cervical cancer, and BAP31 expression was positively correlated with the clinical stages of cervical cancer (Dang et al, 2018). Subsequently, Chen et al (2019) demonstrated that BAP31 can promote the proliferation of gastric cancer cells by interacting with cyclin kinase inhibitor p27 kip1 . Xu et al (2019) found that miR-451a binds to the 5 ′ -UTR of BAP31, induces the endoplasmic reticulum (ER) stress, and leads to the inhibition of cell proliferation in colorectal cancer.…”

B-Cell Receptor-Associated Protein 31 Negatively Regulates the Expression of Monoamine Oxidase A Via R1

“…To explore the mechanism of Bap31 on MAOA, we firstly detected the regulation of Bap31 on the degradation of MAOA. Although Bap31 affects the degradation of many proteins (Wang et al, 2008;Chen et al, 2019), the regulation of Bap31 on MAOA expressions does not appear to be dependent on these effects. Bap31 did not directly affect the ubiqutin-mediated degradation of MAOA in MAOA-HA stable cells with knockdown or overexpression of Bap31 (Figures 3A,B).…”