Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

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 α-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.

Original publication




Journal article


Cancer Res

Publication Date





331 - 345


A549 Cells, Adenoviridae, Animals, Carcinoma, Ovarian Epithelial, Cell Line, Tumor, Female, Genome, Viral, Glutamine, Glycolysis, Heterografts, Humans, Lung Neoplasms, Mice, Mice, Nude, Oncolytic Viruses, Ovarian Neoplasms, Oxidative Phosphorylation, Random Allocation, Virus Replication