Faculty, Staff and Student Publications

Language

English

Publication Date

2-1-2025

Journal

Cancer Letters

DOI

10.1016/j.canlet.2024.217354

PMID

39603381

PMCID

PMC12707521

PubMedCentral® Posted Date

12-17-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

Heat shock protein 90 (HSP90), a vital chaperone involved in the folding and stabilization of various cellular proteins, regulates key functions in many tumor cells. In the context of gastric adenocarcinoma (GAC), where HSP90's role remains largely unexplored, we aimed to investigate the significance of HSP90 inhibitor, AUY922, in regulating the YAP1/TEAD pathway and its association with the tumor immune microenvironment (TME). Our results showed that AUY922 effectively inhibited GAC aggressiveness in both the invitro and invivo models, induced apoptosis, and cell-cycle arrest. Various functional assays elucidated that AUY922 potently inhibited the expression and interaction among YAP1/TEAD and HSP90, resulting in down-regulation of target functional genes. AUY922 additionally altered the tumor microenvironment (TME) into an inflamed state with increased cytokine production in T cells, including interferon gamma, granzyme B, and perforin, and inhibited M2 polarization of tumor-associated macrophages, rendering it a favorable partner for immune checkpoint inhibition. Our findings highlighted the suggestion of targeting HSP90 in GAC therapy via down-regulating YAP1/TEAD signaling. Additionally, our results suggest that AUY922's ability to reshape the GAC TME favoring the host sets the stage for a clinical trial that combines HSP90 and checkpoint inhibition, where HSP90 could serve as a biomarker for patient selection.

Keywords

Stomach Neoplasms, Humans, HSP90 Heat-Shock Proteins, YAP-Signaling Proteins, Tumor Microenvironment, Transcription Factors, Adaptor Proteins, Signal Transducing, Cell Line, Tumor, Isoxazoles, Animals, Resorcinols, Apoptosis, Mice, Cell Proliferation, Signal Transduction, Adenocarcinoma, Xenograft Model Antitumor Assays, Gene Expression Regulation, Neoplastic, TEA Domain Transcription Factors, Heat shock protein 90, AUY922, Gastric cancer, YAP, TEAD, Tumor immune microenvironment

Published Open-Access

yes

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