title: MATE2 Expression Is Associated with Cancer Cell Response to Metformin.
abstract: BACKGROUND
  There is great interest in repurposing the commonly prescribed anti-diabetic drug metformin for cancer therapy. Intracellular uptake and retention of metformin is affected by the expression of organic cation transporters (OCT) 1-3 and by multidrug and toxic compound extrusion (MATE) 1-2. Inside cells, metformin inhibits mitochondrial function, which leads to reduced oxygen consumption and inhibition of proliferation. Reduced oxygen consumption can lead to improved tumor oxygenation and radiation response.
  
  
  OBJECTIVE
  Here we sought to determine if there is an association between the effects of metformin on inhibiting oxygen consumption, proliferation and expression of OCTs and MATEs in a panel of 19 cancer cell lines.
  
  
  RESULTS
  There was relatively large variability in the anti-proliferative response of different cell lines to metformin, with a subset of cell lines being very resistant. In contrast, all cell lines demonstrated sensitivity to the inhibition of oxygen consumption by metformin, with relatively small variation. The expression of OCT1 correlated with expression of both OCT2 and OCT3. OCT1 and OCT2 were relatively uniformly expressed, whereas expression of OCT3, MATE1 and MATE2 showed substantial variation across lines. There were statistically significant associations between resistance to inhibition of proliferation and MATE2 expression, as well as between sensitivity to inhibition of oxygen consumption and OCT3 expression. One cell line (LNCaP) with high OCT3 and low MATE2 expression in concert, had substantially higher intracellular metformin concentration than other cell lines, and was exquisitely sensitive to both anti-proliferative and anti-respiratory effects. In all other cell lines, the concentration of metformin required to inhibit oxygen consumption acutely in vitro was substantially higher than that achieved in the plasma of diabetic patients. However, administering anti-diabetic doses of metformin to tumor-bearing mice resulted in intratumoral accumulation of metformin and reduced hypoxic tumor fractions.
  
  
  CONCLUSIONS
  All cancer cells are susceptible to inhibition of oxygen consumption by metformin, which results in reduced hypoxic tumor fractions beneficial for the response to radiotherapy. High MATE2 expression may result in resistance to the anti-proliferative effect of metformin and should be considered as a negative predictive biomarker in clinical trials.
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.|Institute of Medical Science, University of Toronto, Toronto, Canada.
authors.forename: Sanjana
authors.initials: S
authors.lastname: Chowdhury
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.|Institute of Medical Science, University of Toronto, Toronto, Canada.
authors.forename: Eric
authors.initials: E
authors.lastname: Yung
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
authors.forename: Melania
authors.initials: M
authors.lastname: Pintilie
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.|Institute of Medical Science, University of Toronto, Toronto, Canada.
authors.forename: Hala
authors.initials: H
authors.lastname: Muaddi
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.|University of Maastricht, Maastricht, The Netherlands.
authors.forename: Selim
authors.initials: S
authors.lastname: Chaib
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
authors.forename: ManTek
authors.initials: M
authors.lastname: Yeung
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.|University of Maastricht, Maastricht, The Netherlands.
authors.forename: Manlio
authors.initials: M
authors.lastname: Fusciello
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
authors.forename: Jenna
authors.initials: J
authors.lastname: Sykes
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
authors.forename: Bethany
authors.initials: B
authors.lastname: Pitcher
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.|University of Maastricht, Maastricht, The Netherlands.
authors.forename: Anna
authors.initials: A
authors.lastname: Hagenkort
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
authors.forename: Trevor
authors.initials: T
authors.lastname: McKee
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
authors.forename: Ravi
authors.initials: R
authors.lastname: Vellanki
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
authors.forename: Eric
authors.initials: E
authors.lastname: Chen
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.|Institute of Medical Science, University of Toronto, Toronto, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Canada.|Department of Radiation Oncology, University of Toronto, Toronto, Canada.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Bristow
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.|University of Maastricht, Maastricht, The Netherlands.|Department of Medical Biophysics, University of Toronto, Toronto, Canada.|Department of Radiation Oncology, University of Toronto, Toronto, Canada.
authors.forename: Bradly G
authors.initials: BG
authors.lastname: Wouters
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.|Institute of Medical Science, University of Toronto, Toronto, Canada.|Department of Radiation Oncology, University of Toronto, Toronto, Canada.
authors.forename: Marianne
authors.initials: M
authors.lastname: Koritzinsky
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D019008:Drug Resistance, Neoplasm; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D008687:Metformin / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism; D050810:Octamer Transcription Factors / Q000235:genetics / Q000378:metabolism; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D007004:Hypoglycemic Agents; D050810:Octamer Transcription Factors; D027701:Organic Cation Transport Proteins; C521869:SLC47A1 protein, human; C521870:SLC47A2 protein, human; D008687:Metformin