GLP1R boosts survival, migration and invasion of endometrial cancer cells and protects against ferroptotic cell death

Abstract

Background

Despite the strong evidence concerning carcinogenic roles of glucagon-like peptide 1 receptor (GLP1R), the role of this gene in endometrial cancer (EC) remains elusive. This study investigated the properties of GLP1R on EC in vitro.

Methods

The expression of GLP1R in EC was detected by RT-qPCR, immunohistochemistry, and western blotting. Cell viability, cell cycle, apoptosis, migration, invasion and ferroptosis were assessed through CCK-8, flow cytometry, wound healing, transwell, DCFH-DA and western blotting, respectively.

Results

We found that GLP1R was up-regulated in EC than normal specimens. It had the highest expression in AN3CA cells. Cell viability, migration and invasion were significantly reduced, while cell cycle arrest and apoptosis were induced following GLP1R knockdown. The malignant biological behaviours of AN3CA cells were investigated when treated with exendin-4 (GLP1R agonist). Moreover, GLP1R lowered intracellular ROS level and expression of SLC7A11, and FTH1, but mitigated GPX4 expression in AN3CA cells.

Conclusion

In a word, GLP1R was up-regulated in EC and its up-regulation facilitated the proliferative and metastatic potentials, and protected cells from ferroptosis, thereby accelerating EC progression. These data emphasised the potency of GLP1R as a therapeutic agent against EC.

PLAIN LANGUAGE SUMMARY

Endometrial cancer (EC) is the second most common form of gynaecologic malignancy, with over 189,000 new cases and about 45,000 deaths worldwide per annum. The effects of glucagon-like peptide 1 receptor (GLP1R) in cancers such as colon and pancreatic cancers have been uncovered. However, whether GLP1R affects EC progression especially ferroptosis process remains elusive. In this study, up-regulation of GLP1R promotes the proliferative and metastatic potentials of EC cells, and protects EC cells from ferroptosis. The opposite results are observed in GLP1R knocking-down. Our study found that GLP1R may exert an oncogene function in EC cells, which can affect proliferative, migrated as well as invasive capacities of EC cells. Moreover, it protected EC cells from ferroptosis. Thus, our results expanded the understanding of the function of GLP1R protein and offered insights into the targeted treatment strategies against EC.

Keywords:

• Endometrial cancer
• GLP1R
• ferroptosis

Authors’ contributions

Xinmei Zhang made substantial contributions to the conception and design of the work. Wu Li made substantial contributions to the acquisition, analysis and interpretation of data for the work, and drafted the manuscript. Wen Lyu, Songjun Liu and Fan Ruan revised the manuscript critically for important intellectual content. All authors have read the manuscript, agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy and agreed final approval of the version to be published.

Ethial approval

This research was abided by the Declaration of Helsinki and supported by Tongde Hospital of Zhejiang Province’s Ethics Committee (approval number: 2019038). All participants provided written informed consent.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The datasets analysed during the current study are available from the corresponding author on reasonable request.

Additional information

Funding

This work was funded by Basic Public Welfare Research Project of Zhejiang Province [LGF20H160013]; Medicine and Health Science and Technology Plan Project of Zhejiang Province [2018ZD016].