An Oncogenic Virus Promotes Cell Survival and Cellular Transformation by Suppressing Glycolysis

PLoS Pathogens

Chun Lu¹  Pinghui Feng²  Jae U. Jung²  Shou-Jiang Gao²  Ying Zhu²  Meilan He²  Suzane Ramos da Silva²  Qiming Liang² 

[1] Department of Microbiology and Immunology, Nanjing Medical University, Nanjing, Jiansu, People's Republic of China;Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America

关键词: Glucose;    Glucose metabolism;    Glycolysis;    Transcription factors;    MicroRNAs;    Apoptosis;    Cell proliferation;    Hyperexpression techniques;   

DOI  :  10.1371/journal.ppat.1005648

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY