Metabolic determinants of cancer cell sensitivity to glucose limitation and biguanides
Authors: Tim Wang
Prathapan Thiru
Burcu Yucel
Erol C Bayraktar
Richard Possemato
Franziska K Lorbeer
Clary B Clish
David M Sabatini
Kıvanç Birsoy
Walter W Chen
Journal: Nature (2014)
Discipline: Multidisciplinary
Keywords: glucose; cancer cells; metabolism; tumour microenvironment; Nutrostat
Affiliations: 1] Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA [2] Howard Hughes Medical Institute and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [3] Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142, USA [4] The David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA [5]., Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA., 1] Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA [2] Howard Hughes Medical Institute and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [3] Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142, USA [4] The David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA., Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142, USA.

Abstract:  As the concentrations of highly consumed nutrients, particularly glucose, are generally lower in tumours than in normal tissues, cancer cells must adapt their metabolism to the tumour microenvironment. A better understanding of these adaptations might reveal cancer cell liabilities that can be exploited for therapeutic benefit. Here we developed a continuous-flow culture apparatus (Nutrostat) for maintaining proliferating cells in low-nutrient media for long periods of time, and used it to undertake competitive proliferation assays on a pooled collection of barcoded cancer cell lines cultured in low-glucose conditions. Sensitivity to low glucose varies amongst cell lines, and an RNA interference (RNAi) screen pinpointed mitochondrial oxidative phosphorylation (OXPHOS) as the major pathway required for optimal proliferation in low glucose. We found that cell lines most sensitive to low glucose are defective in the OXPHOS upregulation that is normally caused by glucose limitation as a result of either mitochondrial DNA (mtDNA) mutations in complex I genes or impaired glucose utilization. These defects predict sensitivity to biguanides, antidiabetic drugs that inhibit OXPHOS, when cancer cells are grown in low glucose or as tumour xenografts. Notably, the biguanide sensitivity of cancer cells with mtDNA mutations was reversed by ectopic expression of yeast NDI1, a ubiquinone oxidoreductase that allows bypass of complex I function. Thus, we conclude that mtDNA mutations and impaired glucose utilization are potential biomarkers for identifying tumours with increased sensitivity to OXPHOS inhibitors. 

Retracted: No

PubPeer comments:
  Competing interests The authors declare no competing financial interests. However, part of the authors submitted a patent on 2013-02-25 entitled  Identification and treatment of tumors sensitive to glucose limitation https: patents.google.com patent US20140348749A1 According to the Nature Research guidelines:  For patents and patent applications, disclosure of the following information is requested: patent applicant (whether author or institution), name of inventor(s), application number, status of application, specific aspect of manuscript covered in patent application. https: www.nature.com nature-research editorial-policies competing-interests Finally, it s intriguing that the error bars are so different between the patent and the paper data. Could authors please provide an explanation? ![file] ,