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

• Published in: British journal of cancer 2020-01, Vol.122 (1), p.62-71
• Main Authors: Sivalingam, Vanitha N., Latif, Ayşe, Kitson, Sarah, McVey, Rhona, Finegan, Katherine G., Marshall, Kay, Lisanti, Michael P., Sotgia, Federica, Stratford, Ian J., Crosbie, Emma J.
• Format: Article
• Language: English
• Subjects: 692/4028/67/1517/1931; 692/4028/67/2327; Adaptation; Antidiabetics; Antigens, Neoplasm - genetics; Antigens, Neoplasm - metabolism; Biomedical and Life Sciences; Biomedicine; Cancer; Cancer Research; Carbonic Anhydrase IX - genetics; Carbonic Anhydrase IX - metabolism; Cell Hypoxia - drug effects; Cell Hypoxia - genetics; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Cell viability; Cytostatic Agents - administration & dosage; Cytostatic Agents - therapeutic use; Drug Resistance; Endometrial cancer; Endometrial Neoplasms - drug therapy; Endometrial Neoplasms - metabolism; Endometrial Neoplasms - pathology; Endometrium; Energy metabolism; Epidemiology; Female; Gene Expression Regulation, Neoplastic; Glucose; Glucose - metabolism; Glycolysis; Humans; Hyperglycemia; Hyperglycemia - metabolism; Hypoglycemic Agents - administration & dosage; Hypoglycemic Agents - therapeutic use; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Ki-67 Antigen - metabolism; Metabolism; Metformin; Metformin - administration & dosage; Metformin - adverse effects; Metformin - therapeutic use; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Molecular Medicine; Oncology; Preoperative Care - methods; Signal Transduction - drug effects; Treatment Outcome; Tumor cell lines; Tumors
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/s41416-019-0627-y

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 (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. Conclusions Understanding the metabolic adaptations of endometrial tumours may identify patients likely to derive clinical benefit from metformin.