1. Hypoxia and hyperglycaemia determine why some endometrial tumours fail to respond to metformin
- Author
-
Katherine G. Finegan, Ayse Latif, Emma J Crosbie, Rhona J McVey, Ian J. Stratford, Michael P. Lisanti, Sarah Kitson, Vanitha N Sivalingam, Kay Marshall, and Federica Sotgia
- Subjects
Cancer Research ,endocrine system diseases ,Mitochondrion ,0302 clinical medicine ,Endometrial cancer ,Glycolysis ,0303 health sciences ,Manchester Cancer Research Centre ,digestive, oral, and skin physiology ,Cancer metabolism ,Cell Hypoxia ,Metformin ,3. Good health ,Mitochondria ,Gene Expression Regulation, Neoplastic ,mitochondria ,Treatment Outcome ,Oncology ,030220 oncology & carcinogenesis ,endometrial cancer ,Female ,medicine.symptom ,medicine.drug ,Signal Transduction ,medicine.medical_specialty ,Cell Survival ,Article ,03 medical and health sciences ,Antigens, Neoplasm ,Internal medicine ,Cell Line, Tumor ,Preoperative Care ,medicine ,Humans ,Hypoglycemic Agents ,Viability assay ,Carbonic Anhydrase IX ,030304 developmental biology ,Cell Proliferation ,business.industry ,hypoxia ,ResearchInstitutes_Networks_Beacons/mcrc ,nutritional and metabolic diseases ,Metabolism ,Hypoxia (medical) ,medicine.disease ,Cytostatic Agents ,Hypoxia-Inducible Factor 1, alpha Subunit ,Endometrial Neoplasms ,Endocrinology ,Glucose ,Ki-67 Antigen ,Mitochondrial biogenesis ,Hyperglycemia ,business ,metformin ,hyperglycaemia - Abstract
BackgroundHigh 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.MethodsEndometrial 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.ResultsIn 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.ConclusionsUnderstanding the metabolic adaptations of endometrial tumours may identify patients likely to derive clinical benefit from metformin.
- Published
- 2020