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

Vanitha Sivalingam, Ayse Latif, Sarah Kitson, Rhona J McVey, Katherine Finegan, Kay Marshall, Michael P Lisanti, Federica Sotgia, Ian Stratford, Emma Crosbie

Research output: Contribution to journalArticlepeer-review


Background: 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.
Methods: 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.
Results: 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 (25mM glucose). In low glucose (5.5mM), 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.
Conclusions: Understanding the metabolic adaptations of endometrial tumours may identify patients likely to derive clinical benefit from metformin.
Original languageEnglish
Article number122
Pages (from-to)62-71
Number of pages10
JournalBritish Journal of Cancer
Early online date10 Dec 2019
Publication statusPublished - 7 Jan 2020


  • endometrial cancer
  • metformin
  • hyperglycaemia
  • hypoxia
  • mitochondria

Research Beacons, Institutes and Platforms

  • Manchester Cancer Research Centre


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