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Viral Reprogramming of Metabolism as an Approach to Identify Metabolic Vulnerabilities in Cancer

  • Author(s): Thaker, Shivani K
  • Advisor(s): Christofk, Heather R
  • et al.

Cancer cells and viruses reprogram cell metabolism towards increased nutrient uptake

and anabolism. Unlike cancer cells, viruses undergo intense selection for efficiency, only

upregulating metabolic nodes critical for their rapid replication. Viruses are therefore powerful

tools to identify essential metabolic pathways in cancer cells. A previous study from our lab

reported that adenovirus infection increases host cell anabolic glucose metabolism. Specific

glycolytic genes are activated by binding of viral protein E4ORF1 with cellular transcription

factor MYC, which is upregulated in many cancers. Here, we show that adenovirus infection

also upregulates glutamine metabolism through E4ORF1-induced MYC activation, leading to

increased levels of glutaminase and glutamine transporters. Inhibition of glutaminase reduces

optimal replication of adenovirus and other diverse viruses, including HSV-1 and influenza.

Glutaminase inhibitors are also currently in clinical trials to treat certain types of cancers. This

study serves as a proof-of-principle that metabolic enzymes and pathways important for adenovirus infection converge on critical metabolic enzymes in cancer.

The specific compilation of metabolic genes altered by adenovirus infection, that may

also be critical for cancer cell proliferation, is currently undefined. We find that adenovirus

infection leads to upregulation of an enzyme involved in fructose metabolism, ketohexokinase,

which supports optimal virus replication and lung tumor growth. We further show that lung

cancer cells can convert glucose via the polyol pathway into fructose, which can then be

metabolized by ketohexokinase. Our model for how ketohexokinase promotes anabolism is by

allowing cells to bypass negative feedback on a heavily regulated enzyme in glycolysis,

phosphofructokinase, and allowing increased glucose utilization into nucleotides. Since KHK

deficiency is a clinically benign, targeting KHK in lung cancer have limited systemic toxicities in patients.

Finally, numerous viruses in addition to adenovirus have been found to reprogram host cell metabolism, but whether the flavivirus Zika virus alters metabolism and whether viruses have unique effects on different host cells remains unclear. We find that Zika virus differentially alters glucose metabolism in both human cells and mosquito cells by increasing glucose use in the TCA cycle in human cells, while increasing glucose utilization into the pentose phosphate pathway in mosquito cells. Zika virus infection of human cells leads to selective depletion of nucleotide triphosphates, leading to AMP-activated protein kinase activation and cell death. Our findings suggest that the differential metabolic reprogramming during Zika virus infection of human versus mosquito cells determines whether or not cell death occurs and demonstrates that viruses can have contrasting effects depending on the host cell. Taken together, this dissertation (i) describes virally induced metabolic changes in both adenovirus and Zika virus and (ii) utilizes the evolutionary efficiency of adenovirus infection as an approach to identify important metabolic enzymes in anabolism and cancer.

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