Unfolded Protein Response Is Activated by Aurora Kinase A in Esophageal Adenocarcinoma

Abstract

Unfolded protein response (UPR) protects malignant cells from endoplasmic reticulum stress-induced apoptosis. We report that Aurora kinase A (AURKA) promotes cancer cell survival by activating UPR in esophageal adenocarcinoma (EAC). A strong positive correlation between AURKA and binding immunoglobulin protein (BIP) mRNA expression levels was found in EACs. The in vitro assays indicated that AURKA promoted IRE1α protein phosphorylation, activating prosurvival UPR in FLO-1 and OE33 cells. The use of acidic bile salts to mimic reflux conditions in patients induced high AURKA and IRE1α levels. This induction was abrogated by AURKA knockdown in EAC cells. AURKA and p-IRE1α protein colocalization was observed in neoplastic gastroesophageal lesions of the L2-IL1b mouse model of Barrett’s esophageal neoplasia. The combined treatment using AURKA inhibitor and tunicamycin synergistically induced cancer cell death. The use of alisertib for AURKA inhibition in the EAC xenograft model led to a decrease in IRE1α phosphorylation with a significant reduction in tumor growth. These results indicate that AURKA activates UPR, promoting cancer cell survival during ER stress in EAC. Targeting AURKA can significantly reverse prosurvival UPR signaling mechanisms and decrease cancer cell survival, providing a promising approach for the treatment of EAC patients.

Pan-cancer analysis and in vitro validation of the oncogenic and prognostic roles of AURKA in human cancers

“…Additionally, Lu H et al. conducted an investigation into AURKA’s function in EAC ( 19 ). Their analysis of AURKA expression and binding immunoglobulin protein (BIP) in EAC revealed a positive correlation between AURKA and a cellular phenomenon known as the unfolded protein response (UPR).…”

“…Furthermore, their study lacks experimental validation. Additionally, in ESCA, most studies have concentrated on AURKA’s role in esophageal squamous cell carcinoma, with limited attention given to EAC ( 6 , 18 , 19 ). Particularly, there is a paucity of literature that comprehensively synthesizes the clinical significance and molecular biological functions of AURKA in EAC and other malignancies.…”

The dual effect of endoplasmic reticulum stress in digestive system tumors and intervention of Chinese botanical drug extracts: a review

“…Several studies have confirmed the activating and facilitating role of ERS and its downstream responses in EC: Lu H et al (2022) found that aurora kinase A (AURKA), a mitotic kinases mediating several protumor genic functions, promotes UPR through IRE1 phosphorylation in vitro and in vivo , resulting in adaptive survival of EAC cells FLO-1, LO33 and SK-GT4. Chen SM et al (2023) found that Fusobacterium nucleatum (Fn)-induced ERS-related proteins GRP78 and XBP1 high expression could promote the malignant evolution of KYSE150 and KYSE140 in ESSC cells.…”

Cranberry Proanthocyanidins Mitigate Reflux-Induced Transporter Dysregulation in an Esophageal Adenocarcinoma Model

“…CD44, a commonly upregulated protein in EAC [95], also has direct protein interactions with ABCB1, ABCC1, SLC2A1, SLC7A11 and SLC9A1. All transporters, except for SLC6A20, have either direct or indirect interactions with key regulatory proteins previously reported in EAC, including the transcription factors ATF4 and NFκB, unfolded protein response-related proteins (ERN1 or IRE1, ATF4) and multiple inflammation, bacterial and immune-linked proteins (i.e., PTGS2/Cox2, MYD88, IL-8 or CXCL8, IL-1β, CD44) [96][97][98][99]. The string network further illustrates the connectivity between families of transporters (ABCs and SLCs).…”