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EV017/#1282  GLP-1 analogues reduce the incidence of endometrial cancer in an animal model
  1. Michael Wilkinson1,
  2. Karen Mulligan1,
  3. Bruce Moran1,
  4. Oleksii S Rukhlenko1,
  5. Eugene Kashdan1,
  6. Boris N Kholodenko1,
  7. Aurelie Fabre2,
  8. Janet Mccormack2,
  9. Niall Docherty1,
  10. Carel Le Roux3 and
  11. Donal Brennan1
  1. 1Ireland East Gynaecological Oncology Group, UCD School of Medicine, Catherine McAuley Research Centre, Mater Misericordiae University Hospital, Dublin, Ireland
  2. 2Conway Institute, Research Pathology Core Facility, Dublin, Ireland
  3. 3Dept of Experimental Pathology, Conway Institute, Diabetes Complications Research Centre, Dublin, Ireland

Abstract

Introduction GLP-1 analogues can stimulate apoptosis and autophagy in endometrial cancer cell lines. We sought to assess the effect of liraglutide on endometrial cancer development and local microenvironment in the BDII/HAN rat model.

Methods 38 BDII/Han rats were randomised into two groups at 12 months of age - a standard group (n=17) and a liraglutide + diet restriction group (n=21). Animals were sacrificed at 15 months of age, RNAseq, whole and phospho-proteomics performed on endometrial cancers and normal endometrium. Cell state transition assessment and regulation (cSTAR), analysis of transcriptomic, proteomic and phosphor-proteomic data was used to assess the mechanism of action of liraglutide on the endometrium (Rukhlenko et al. 2022 Nature https://doi.org/10.1038/s41586-022-05194-y).

Results Liraglutide treatment caused a 15% weight loss and reduced incidence of endometrial cancer from 53% (9/17) in the standard group to 20% (4/20) in the intervention group, all of which were poorly differentiated serous, immune excluded cancers. cSTAR analysis demonstrated that Liraglutide upregulates transcription of numerous genes, while their abundance at proteomic and phosphoproteomic levels are strongly downregulated and inhibits autophagy in normal endometrium. Liraglutide also inhibits estrogen signalling which in combination with inhibition of autophagy may support the development of serous cancers in an atrophic endometrium

Conclusion/Implications GLP-1 analogues reduce the rate of endometrial cancer in BDII/HAN rodent models however the cancers that developed in the liraglutide group were poorly differentiated, immune excluded serous cancers. Further data is required to establish the potential role of GLP-1 induced weight loss as an adjunctive treatment in endometrial cancer.

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