Hypoxia and hyperglycaemia determine why some endometrial tumours fail to respond to metformin

Sivalingam, VN; Latif, A; Kitson, S; McVey, R; Finegan, KG; Marshall, K; Lisanti, MP; Sotgia, F; Stratford, IJ; Crosbie, EJ

Abstract

High expression of Ki67, a proliferation marker, is associated with reduced endometrial cancer-specific survival. Pre-surgical metformin reduces tumour Ki-67 expression in some women with endometrial cancer. Metformin's anti-cancer activity may relate to effects on cellular energy metabolism. Since tumour hypoxia and glucose availability are major cellular redox determinants, we evaluated their role in endometrial cancer response to metformin. Endometrial cancer biopsies from women treated with pre-surgical metformin were tested for the hypoxia markers, HIF-1α and CA-9. Endometrial cancer cell lines were treated with metformin in variable glucose concentrations in normoxia or hypoxia and cell viability, mitochondrial biogenesis, function and energy metabolism were assessed. In women treated with metformin (n = 28), Ki-67 response was lower in hypoxic tumours. Metformin showed minimal cytostatic effects towards Ishikawa and HEC1A cells in conventional medium (25 mM glucose). In low glucose (5.5 mM), a dose-dependent cytostatic effect was observed in normoxia but attenuated in hypoxia. Tumours treated with metformin showed increased mitochondrial mass (n = 25), while in cultured cells metformin decreased mitochondrial function. Metformin targets mitochondrial respiration, however, in hypoxic, high glucose conditions, there was a switch to glycolytic metabolism and decreased metformin response. Understanding the metabolic adaptations of endometrial tumours may identify patients likely to derive clinical benefit from metformin.

Citation

Sivalingam, V., Latif, A., Kitson, S., McVey, R., Finegan, K., Marshall, K., …Crosbie, E. (2020). Hypoxia and hyperglycaemia determine why some endometrial tumours fail to respond to metformin. British Journal of Cancer, 122(1), 62-71. https://doi.org/10.1038/s41416-019-0627-y

• Journal Article Type: Article
• Acceptance Date: Oct 21, 2019
• Online Publication Date: Dec 10, 2019
• Publication Date: Jan 7, 2020
• Deposit Date: Jan 3, 2020
• Publicly Available Date: Jan 3, 2020
• Journal: British Journal of Cancer
• Print ISSN: 0007-0920
• Electronic ISSN: 1532-1827
• Publisher: Cancer Research UK
• Volume: 122
• Issue: 1
• Pages: 62-71
• DOI: https://doi.org/10.1038/s41416-019-0627-y
• Publisher URL: https://doi.org/10.1038/s41416-019-0627-y
• Related Public URLs: https://www.nature.com/bjc/
• Additional Information: Additional Information : ** From PubMed via Jisc Publications Router **Journal IDs: eissn 1532-1827 **Article IDs: pubmed: 31819173; pii: 10.1038/s41416-019-0627-y **History: accepted 21-10-2019; revised 30-08-2019; submitted 08-06-2019; Grant Number: NIHR-CS-012-009; Grant Number: RTF 352/098670/Z/12/Z; Grant Number: IS-BRC-1215-20007