Targeting integrin αvβ3 with indomethacin inhibits patient-derived xenograft tumour growth and recurrence in oesophageal squamous cell carcinoma.

Abstract

RATIONALE:

A high risk of post-operative recurrence contributes to the poor prognosis and low survival rate of oesophageal squamous cell carcinoma (ESCC) patients. Increasing experimental evidence suggests that integrin adhesion receptors, in particular integrin αv (ITGAV), are important for cancer cell survival, proliferation and migration. Therefore, targeting ITGAV may be a rational approach for preventing ESCC recurrence.

MATERIALS AND METHODS:

Protein levels of ITGAV were determined in human ESCC tumour tissues using immunohistochemistry. MTT, propidium iodide staining, and annexin V staining were utilized to investigate cell viability, cell cycle progression, and induction of apoptosis, respectively. Computational docking was performed with the Schrödinger Suite software to visualize the interaction between indomethacin and ITGAV. Cell-derived xenograft mouse models, patient-derived xenograft (PDX) mouse models, and a humanized mouse model were employed for in vivo studies.

RESULTS:

ITGAV was upregulated in human ESCC tumour tissues and increased ITGAV protein levels were associated with poor prognosis. ITGAV silencing or knockout suppressed ESCC cell growth and metastatic potential. Interestingly, we identified that indomethacin can bind to ITGAV and enhance synovial apoptosis inhibitor 1 (SYVN1)-mediated degradation of ITGAV. Integrin β3, one of the β subunits of ITGAV, was also decreased at the protein level in the indomethacin treatment group. Importantly, indomethacin treatment suppressed ESCC tumour growth and prevented recurrence in a PDX mouse model. Moreover, indomethacin inhibited the activation of cytokine TGFβ, reduced SMAD2/3 phosphorylation, and increased anti-tumour immune responses in a humanized mouse model.

CONCLUSION:

ITGAV is a promising therapeutic target for ESCC. Indomethacin can attenuate ESCC growth through binding to ITGAV, promoting SYVN1-mediated ubiquitination of ITGAV, and potentiating cytotoxic CD8+ T cell responses.

• Authors: Fangfang Liu, Qiong Wu, Wei Han, Kyle Laster, Yamei Hu, Fayang Ma, Hanyong Chen, Xueli Tian, Yan Qiao, Hui Liu, Dong Joon Kim, Zigang Dong, Kangdong Liu
• Journal: Clinical and translational medicine (Clin Transl Med) Vol. 11 Issue 10 Pg. e548 (10 2021) ISSN: 2001-1326 [Electronic] United States
• PMID: 34709754 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Integrin alphaVbeta3
• Indomethacin

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Disease Models, Animal
• Esophageal Neoplasms (drug therapy)
• Esophageal Squamous Cell Carcinoma (drug therapy)
• Heterografts
• Humans
• Indomethacin (pharmacology)
• Integrin alphaVbeta3 (drug effects, metabolism)
• Mice, Nude
• Neoplasm Recurrence, Local (prevention & control)
• Mice