*2.3. Oncogene-Mediated Stimulation of Anabolism: Supplying the Metabolic Needs of Replicating Viruses*

Both viral replication and tumor-cell growth are anabolic processes, i.e., dependent on the biosynthesis of macromolecules (nucleic acids, proteins, lipids and oligosaccharides). As such, both oncogenic transformation and viral infection optimize the cell's metabolic regulation towards their anabolic needs. The efficiency and extent by which oncogene-induced processes carry out such reprograming is predicted to support enhanced replication of OVs. For example, oncogenic KRAS stimulates anabolic metabolism to maintain pancreatic tumors through activation of MAPK and MYC pathways and the ensuing

increased expression of genes which regulate sterol biosynthesis, pyrimidine metabolism and glycosylation [65]. Such metabolically reprogramed cells are characterized by increased glycolytic flux (Warburg effect, [66]) and by glutamine serving as a major carbon source for the tri-carboxylic acid (TCA) cycle [67]. Multiple lines of evidence support the notion that viruses benefit from analogous metabolic reprograming, as different viruses manipulate cell metabolism towards aerobic glycolysis (reviewed in [68,69]) and reprogram glutamine catabolism to optimize virus replication [70]. Similarly, fatty acid synthase (FASN), which regulates the production of long-chain fatty acids [71], is overexpressed in different tumors [71,72], and induced upon oncogenic-RAS-mediated cell transformation [73,74]. Analogous to its role in tumorigenesis, FASN-mediated lipogenesis is required for infection with diverse viruses [75–79]. The similitude of the metabolic requirements of KRAS-transformed tumors and viruses is further exemplified by the effects of inhibitors of dihydroorotate dehydrogenase (DHODH), which perturb *de novo* pyrimidine biosynthesis, selectively inhibit the growth of KRAS mutant cell lines [80] and exhibit broad-range antiviral activity against RNA viruses [81]. suing increased expression of genes which regulate sterol biosynthesis, pyrimidine metabolism and glycosylation [65]. Such metabolically reprogramed cells are characterized by increased glycolytic flux (Warburg effect, [66]) and by glutamine serving as a major carbon source for the tri-carboxylic acid (TCA) cycle [67]. Multiple lines of evidence support the notion that viruses benefit from analogous metabolic reprograming, as different viruses manipulate cell metabolism towards aerobic glycolysis (reviewed in [68,69]) and reprogram glutamine catabolism to optimize virus replication [70]. Similarly, fatty acid synthase (FASN), which regulates the production of long-chain fatty acids [71], is overexpressed in different tumors [71,72], and induced upon oncogenic-RAS-mediated cell transformation [73,74]. Analogous to its role in tumorigenesis, FASN-mediated lipogenesis is required for infection with diverse viruses [75–79]. The similitude of the metabolic requirements of KRAS-transformed tumors and viruses is further exemplified by the effects of inhibitors of dihydroorotate dehydrogenase (DHODH), which perturb *de novo* pyrimidine biosynthesis, selectively inhibit the growth of KRAS mutant cell lines [80] and exhibit broad-range antiviral activity against RNA viruses [81].

The multiple effects of oncogenic RAS, which promote viral replication and reduce tumor-cell immunogenicity are schematically depicted in Figure 1. The multiple effects of oncogenic RAS, which promote viral replication and reduce tumor-cell immunogenicity are schematically depicted in Figure 1.

*Cancers* **2021**, *13*, 939 5 of 19

*Replicating Viruses* 

*2.3. Oncogene-Mediated Stimulation of Anabolism: Supplying the Metabolic Needs of* 

Both viral replication and tumor-cell growth are anabolic processes, i.e., dependent on the biosynthesis of macromolecules (nucleic acids, proteins, lipids and oligosaccharides). As such, both oncogenic transformation and viral infection optimize the cell's metabolic regulation towards their anabolic needs. The efficiency and extent by which oncogene-induced processes carry out such reprograming is predicted to support enhanced replication of OVs. For example, oncogenic KRAS stimulates anabolic metabolism to maintain pancreatic tumors through activation of MAPK and MYC pathways and the en-

**Figure 1.** Oncogenic RAS supports viral infection through multiple molecular mechanisms. Scheme depicts mechanisms described throughout review. Green arrows or blunt red arrows denote stimulation or inhibition, respectively. Dashed arrows indicate cases where one source of information supports the connection between oncogenic RAS and its effector, and another source supports the link between the effector and the oncolysis-regulating mechanism. The figure was created with BioRender.com (accessed on 12 February 2021). **Figure 1.** Oncogenic RAS supports viral infection through multiple molecular mechanisms. Scheme depicts mechanisms described throughout review. Green arrows or blunt red arrows denote stimulation or inhibition, respectively. Dashed arrows indicate cases where one source of information supports the connection between oncogenic RAS and its effector, and another source supports the link between the effector and the oncolysis-regulating mechanism. The figure was created with BioRender.com (accessed on 12 February 2021).
