Functional study of apoptosis inducing protein in human cholangiocarcinoma

Abstract

Apoptosis-inducing protein (AIP) is a secreted protein, synthesized by adipocytes and epithelial cells, that is downregulated in breast, colorectal, gastric, liver, and lung cancers, portending a poor prognosis. AIP is a potential biomarker of cancer progression, but its role in cholangiocarcinoma, a cancer of the bile duct, remains unknown. In this study, we found that AIP mRNA, but not protein, is expressed in cholangiocarcinoma. However, AIP protein overexpression induced cell death, apoptosis, and sub-G1 arrest. Importantly, AIP-induced apoptotic changes were blocked by knockdown of the pro-apoptotic protein BID, suggesting that AIP-induced apoptosis occurs via BID-dependent pathways. Mechanistically, ELF25 (E74 Like ETS Transcription Factor 1) directly targets AIP by ubiquitination and degradation. Similarly, AIP protein expression was downregulated in cholangiocarcinoma, thus negatively correlating with ELF25 expression in this cancer. Of note, low AIP, combined with high ELF25, expression, correlated with short patient survival in cholangiocarcinoma. Additionally, ELF25 knockdown led to AIP upregulation, to inhibit growth of cancer cells. Taken together, these results suggest that AIP could be a potential therapeutic target or a diagnostic biomarker, to treat patients with this insidious malignancy. Keywords: apoptosis-inducing protein, apoptosis, therapeutic target, biomarker, cholangiocarcinoma.