title: An Oncogenic Virus Promotes Cell Survival and Cellular Transformation by Suppressing Glycolysis.
abstract: Aerobic glycolysis is essential for supporting the fast growth of a variety of cancers. However, its role in the survival of cancer cells under stress conditions is unclear. We have previously reported an efficient model of gammaherpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV)-induced cellular transformation of rat primary mesenchymal stem cells. KSHV-transformed cells efficiently induce tumors in nude mice with pathological features reminiscent of Kaposi's sarcoma tumors. Here, we report that KSHV promotes cell survival and cellular transformation by suppressing aerobic glycolysis and oxidative phosphorylation under nutrient stress. Specifically, KSHV microRNAs and vFLIP suppress glycolysis by activating the NF-κB pathway to downregulate glucose transporters GLUT1 and GLUT3. While overexpression of the transporters rescues the glycolytic activity, it induces apoptosis and reduces colony formation efficiency in softagar under glucose deprivation. Mechanistically, GLUT1 and GLUT3 inhibit constitutive activation of the AKT and NF-κB pro-survival pathways. Strikingly, GLUT1 and GLUT3 are significantly downregulated in KSHV-infected cells in human KS tumors. Furthermore, we have detected reduced levels of aerobic glycolysis in several KSHV-infected primary effusion lymphoma cell lines compared to a Burkitt's lymphoma cell line BJAB, and KSHV infection of BJAB cells reduced aerobic glycolysis. These results reveal a novel mechanism by which an oncogenic virus regulates a key metabolic pathway to adapt to stress in tumor microenvironment, and illustrate the importance of fine-tuning the metabolic pathways for sustaining the proliferation and survival of cancer cells, particularly under stress conditions.
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Suzane
authors.initials: S
authors.lastname: Ramos da Silva
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Meilan
authors.initials: M
authors.lastname: He
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Qiming
authors.initials: Q
authors.lastname: Liang
authors.affiliation: Department of Microbiology and Immunology, Nanjing Medical University, Nanjing, Jiansu, People's Republic of China.
authors.forename: Chun
authors.initials: C
authors.lastname: Lu
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Pinghui
authors.initials: P
authors.lastname: Feng
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Jae U
authors.initials: JU
authors.lastname: Jung
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Shou-Jiang
authors.initials: SJ
authors.lastname: Gao
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology*; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival; D002472:Cell Transformation, Viral / Q000502:physiology*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D055785:Gene Knockdown Techniques; D006019:Glycolysis / Q000502:physiology; D006566:Herpesviridae Infections / Q000378:metabolism*; D019288:Herpesvirus 8, Human / Q000378:metabolism; D006801:Humans; D054685:Lymphoma, Primary Effusion / Q000378:metabolism / Q000821:virology; D018613:Microscopy, Confocal; D016133:Polymerase Chain Reaction; D051381:Rats