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

ABSTRACT: 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. Integrin αvβ3 was upregulated in ESCC tumour tissue compared to adjacent tissue. Indomethacin binds to ITGAV and promotes SYVN1‐mediated ubiquitination of ITGAV, thereby attenuating the αvβ3/PI3K/AKT/GS3Kβ signalling pathway. Inhibition of αvβ3 by indomethacin treatment blocks TGFβ/SMAD2/SMAD3 signalling and increases anti‐tumour immune responses in a humanized mouse model. Indomethacin suppresses ESCC tumour growth and recurrence in a PDX mouse model.

SUBMITTER: Liu F 

PROVIDER: S-EPMC8552524 | biostudies-literature |

REPOSITORIES: biostudies-literature