PMID- 30487139
OWN - NLM
STAT- MEDLINE
DCOM- 20191031
LR  - 20240210
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Linking)
VI  - 79
IP  - 2
DP  - 2019 Jan 15
TI  - Antagonism of Glycolysis and Reductive Carboxylation of Glutamine Potentiates 
      Activity of Oncolytic Adenoviruses in Cancer Cells.
PG  - 331-345
LID - 10.1158/0008-5472.CAN-18-1326 [doi]
AB  - Tumor cells exhibiting the Warburg effect rely on aerobic glycolysis for ATP 
      production and have a notable addiction to anaplerotic use of glutamine for 
      macromolecular synthesis. This strategy maximizes cellular biosynthetic potential 
      while avoiding excessive depletion of NAD(+) and provides an attractive anabolic 
      environment for viral infection. Here, we evaluate infection of highly permissive 
      and poorly permissive cancer cells with wild-type adenoviruses and the oncolytic 
      chimeric adenovirus enadenotucirev (EnAd). All adenoviruses caused an increase in 
      glucose and glutamine uptake along with increased lactic acid secretion. 
      Counterintuitively, restricting glycolysis using 2-deoxyglucose or by limiting 
      glucose supply strongly improved virus activity in both cell types. Antagonism of 
      glycolysis also boosted EnAd replication and transgene expression within human 
      tumor biopsies and in xenografted tumors in vivo. In contrast, the virus life 
      cycle was critically dependent on exogenous glutamine. Virus activity in 
      glutamine-free cells was rescued with exogenous membrane-permeable 
      alpha-ketoglutarate, but not pyruvate or oxaloacetate, suggesting an important role 
      for reductive carboxylation in glutamine usage, perhaps for production of 
      biosynthetic intermediates. This overlap between the metabolic phenotypes of 
      adenovirus infection and transformed tumor cells may provide insight into how 
      oncolytic adenoviruses exploit metabolic transformation to augment their 
      selectivity for cancer cells. SIGNIFICANCE: This study describes changes in 
      glucose and glutamine metabolism induced by oncolytic and wild-type adenoviruses 
      in cancer cells, which will be important to consider in the preclinical 
      evaluation of oncolytic viruses.
CI  - (c)2018 American Association for Cancer Research.
FAU - Dyer, Arthur
AU  - Dyer A
AUID- ORCID: 0000-0002-1436-1734
AD  - Department of Oncology, University of Oxford, Oxford, United Kingdom.
FAU - Schoeps, Benjamin
AU  - Schoeps B
AD  - Institute of Molecular Immunology and Experimental Oncology, Technische 
      Universitat Munchen, Munchen, Germany.
FAU - Frost, Sally
AU  - Frost S
AD  - Department of Oncology, University of Oxford, Oxford, United Kingdom.
FAU - Jakeman, Philip
AU  - Jakeman P
AUID- ORCID: 0000-0001-7141-4321
AD  - Department of Oncology, University of Oxford, Oxford, United Kingdom.
FAU - Scott, Eleanor M
AU  - Scott EM
AD  - Department of Oncology, University of Oxford, Oxford, United Kingdom.
FAU - Freedman, Joshua
AU  - Freedman J
AD  - Department of Oncology, University of Oxford, Oxford, United Kingdom.
FAU - Jacobus, Egon J
AU  - Jacobus EJ
AD  - Department of Oncology, University of Oxford, Oxford, United Kingdom.
FAU - Seymour, Leonard W
AU  - Seymour LW
AD  - Department of Oncology, University of Oxford, Oxford, United Kingdom. 
      len.seymour@oncology.ox.ac.uk.
LA  - eng
GR  - 29106/CRUK_/Cancer Research UK/United Kingdom
GR  - C552/A17720/CRUK_/Cancer Research UK/United Kingdom
GR  - MR/K501256/1/MRC_/Medical Research Council/United Kingdom
GR  - 17720/CRUK_/Cancer Research UK/United Kingdom
GR  - MR/N013468/1/MRC_/Medical Research Council/United Kingdom
GR  - MR/P012795/1/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20181128
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (enadenotucirev)
RN  - 0RH81L854J (Glutamine)
SB  - IM
MH  - A549 Cells
MH  - Adenoviridae/genetics/*physiology
MH  - Animals
MH  - Carcinoma, Ovarian Epithelial/*metabolism/*virology
MH  - Cell Line, Tumor
MH  - Female
MH  - Genome, Viral
MH  - Glutamine/*metabolism
MH  - Glycolysis
MH  - Heterografts
MH  - Humans
MH  - Lung Neoplasms/*metabolism/*virology
MH  - Mice
MH  - Mice, Nude
MH  - Oncolytic Viruses/genetics/*physiology
MH  - Ovarian Neoplasms/*metabolism/*virology
MH  - Oxidative Phosphorylation
MH  - Random Allocation
MH  - Virus Replication
EDAT- 2018/11/30 06:00
MHDA- 2019/11/02 06:00
CRDT- 2018/11/30 06:00
PHST- 2018/05/09 00:00 [received]
PHST- 2018/09/08 00:00 [revised]
PHST- 2018/11/08 00:00 [accepted]
PHST- 2018/11/30 06:00 [pubmed]
PHST- 2019/11/02 06:00 [medline]
PHST- 2018/11/30 06:00 [entrez]
AID - 0008-5472.CAN-18-1326 [pii]
AID - 10.1158/0008-5472.CAN-18-1326 [doi]
PST - ppublish
SO  - Cancer Res. 2019 Jan 15;79(2):331-345. doi: 10.1158/0008-5472.CAN-18-1326. Epub 
      2018 Nov 28.