Antagonism of Glycolysis and Reductive Carboxylation of Glutamine Potentiates Activity of Oncolytic Adenoviruses in Cancer Cells

Abstract

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 þ 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 membranepermeable a-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.

Metabolic Reprogramming of the Host Cell by Human Adenovirus Infection

“…Another study compared the effects of infection with HAdVC-5, wild-type HAdV species B type 11p (HAdVB-11p) (Table 1), and an oncolytic HAdV, enadenotucirev (EnAd, formerly ColoAd1), on metabolism of A549 cells (Table 2) and SKOV3 ovarian carcinoma cells (Table 2) [45]. HAdV infection increased glycolysis and glutaminolysis [45], as expected [25,26,46,47]. However, counterintuitively, the authors found that inhibiting glycolysis with 2-deoxyglucose (2DG) or limiting glucose availability increased viral genome replication and packaging efficiency in both A549 cells and SKOV3 cells [45].…”

“…HAdV infection increased glycolysis and glutaminolysis [45], as expected [25,26,46,47]. However, counterintuitively, the authors found that inhibiting glycolysis with 2-deoxyglucose (2DG) or limiting glucose availability increased viral genome replication and packaging efficiency in both A549 cells and SKOV3 cells [45]. Inhibition of glycolysis in SKOV3 cells, which, unlike A549 cells, exhibit a metabolic phenotype that does not resemble the Warburg effect [65], also increased the speed of EnAd and HAdVB-11p viral replication and progeny production [45].…”

Hexokinase inhibition using D-Mannoheptulose enhances oncolytic newcastle disease virus-mediated killing of breast cancer cells

“…Its reported that interfering with cancer cells metabolism through glycolysis inhibition may enhance oncolytic virotherapy activity [27]. A recent study showed that using 2-deoxyglucose (2DG) to block glycolysis or through restricting glucose amount will enhance oncolytic adenoviruses activity in permissive and poorly permissive cancer cells [28]. Furthermore, pyruvate dehydrogenase kinase inhibition showed to improve reovirus oncolytic anti-tumor efficacy in several cancer types [29].…”

Delivery and Biosafety of Oncolytic Virotherapy

“…Blockade of immune checkpoints, immunogenic chemotherapy and IFN-α suppression can promote the local therapeutic effect of oncolytic viruses by direct intratumoral injection (41). Antagonizing the glycolysis and carboxylation of glutamine can enhance the activity of an oncolytic adenovirus directly injected into tumors by promoting its lysis in the cancer cells (49).…”